Pyrrolidine compound and a process for preparing the same

ABSTRACT

The present invention relates to a novel pyrrolidine compound, which has a potent antagonistic activity against central cannabinoid (CB1) receptor, having the formula [I]: wherein each of R 1  and R 2  is (A) optionally substituted aryl (or heteroaryl) group, or (B) both of the groups combine to form a group of the formula: one of R 3  and R 4  is hydrogen and another is hydrogen, hydroxyl, hydroxyalkyl, etc., or both of R 3  and R 4  combine to form oxo group, R 5  is hydrogen or alkyl, Y is single bond, oxygen atom or a group of the formula: —N(R 7 )—, R 6  is optionally substituted hydrocarbon group or optionally substituted cyclic group, R 7  is alkyl or alkyloxycarbonylalkyl, provided that R 6  is not 4-amino-5-chloro-2-methoxyphenyl group when Y is single bond and one of the R 3  and R 4  is hydrogen and another is hydroxymethyl, or a pharmaceutically acceptable salt thereof.

TECHNICAL FIELD

The present invention relates to a novel pyrrolidine compound or a pharmaceutically acceptable salt thereof having a potent antagonistic activity against central cannabinoid (CB1) receptor and being useful as a medicament.

BACKGROUND ART

It is well known that, by intake of marijuana, various psychiatric or neurological reactions such as confusion of temporal or space sense, euphoria, alteration of memories, analgesia, hallucination and the like would be produced. The compounds generally referred to as “cannabinoid” including

9-tetrahydrocannabinol (

9-THC) are responsible for many of such reactions. The effect of cannabinoid is considered to be produced by an interaction between the compound and its endogenous specific/high-affinity receptors. Two subtypes of cannabinoid receptors (CB1 and CB2) have been identified and cloned. The CB1 receptor is distributed in central nervous system (CNS) regions including brain (Nature, Vol. 346, 1990, pp 561-564) while the CB2 receptor is distributed in immune system including spleen (Nature, Vol. 365, 1993, pp 61-65).

Substances having affinity to such cannabinoid receptors (agonists, antagonists or inverse agonists) may produce various pharmacological effects like marijuana. In particular, substances having affinity to central CB1 receptor may be useful for treatment of a CNS disease such as a psychotic disorder, a neurological disorder and the like.

Examples of the known substances having affinity to CB1 receptor include a 4,5-dihydro-1H-pyrazole compound (WO01/70700, WO03/026648, WO03/026647), a 1H-imidazole compound (WO03/027076, WO03/007887, WO03/063781, WO03/040107), a pyrazine compound (WO03/051850, WO03/051851), a 1H-pyrazole compound (U.S. Pat. No. 5,624,941, U.S. Pat. No. 6,509,367), a pyridine compound (WO03/084930, WO03/084943, WO03/082191), an azethidine compound (WO01/64632, WO03/020314), an arylamide compound (WO03/087027, WO03/082190), a 1,5,6,7-tetrahydropyrrolo[3,2-c]pyridine compound (WO03/027114), a pyrrole compound (WO03/027069) and a 1,2,4-triazole compound (WO03/082833). Meanwhile, JP1993-17434 discloses that specific pyrrolidine compounds such as 4-amino-5-chloro-N-[1-(diphenylmethyl)-5-(hydroxymethyl)-3-pyrrolidinyl]-2-methoxy-benzamide increased gastric motility in mice, but there are no suggestion on whether or not the pyrrolidine compound has an antagonistic activity against CB1 receptor.

DISCLOSURE OF INVENTION

The present invention provides a novel pyrrolidine compound or a pharmaceutically acceptable salt thereof having a potent antagonistic activity against central cannabinoid (CB1) receptor and being useful as a medicament and a process for preparing the same.

The present invention relates to a compound of the formula [I]:

wherein each of R¹ and R² is (A) independently an aryl (or heteroaryl) group optionally substituted by the same or different one to three group(s) selected from (1) a halogen atom, (2) cyano group, (3) an alkyl group optionally substituted by one to three groups selected from a halogen atom and an alkyloxy group, (4) an alkyloxy group optionally substituted by one to three groups selected from a halogen atom, a cycloalkyl group, an alkyloxy group, a mono- or di-alkylamino group, a pyrrolidinyl group and a morpholino group, (5) an amino group optionally substituted by a group selected from an alkyl group, an alkyloxyalkyl group, a cycloalkyl group and a mono- or di-alkylamino-alkyl group, (6) a carbamoyloxy group optionally substituted by one to two alkyl groups, (7) an alkylsulfonyl group, (8) a cycloalkyloxy group, (9) a carbamoyl group optionally substituted by an alkyl group(s), (10) a nitro group, (11) an alkylthio group, (12) an aminosulfonyl group optionally substituted by an alkyl group(s), (13)) an alkylsulfinyl group, (14) an alkyleneoxy group and (15) an alkylenedioxy group, or (B) both of the groups combine each other together with an adjacent CH group to form a group of the formula:

one of R³ and R⁴ is a hydrogen atom and another is a hydrogen atom, a hydroxyl group, a hydroxyalkyl group, a dialkylaminoalkyl group, an alkyloxy group, an alkyloxyalkyl group, an alkyloxyalkyloxy group, a carboxyl group, an alkyloxycarbonyl group, a saturated or unsaturated, 4- to 10-membered, nitrogen- or oxygen-containing heterocyclic group, a carbamoyl group or a mono- or dialkylcarbamoyl group (the alkyl moiety of said group being optionally substituted by a group selected from a halogen atom, a hydroxyl group, a mono- or di-alkylamino group and a saturated or unsaturated, 4- to 10-membered, nitrogen- or oxygen-containing heterocyclic group) or both of R³ and R⁴ combine each other to form an oxo group, R⁵ is a hydrogen atom or an alkyl group, Y is a single bond, an oxygen atom or a group of the formula: —N(R⁷)—, R⁶ is (1) a straight or branched chain hydrocarbon group optionally having a substituent(s) and optionally containing one or more double or triple bond in the molecule or (2) a cyclic group optionally having a substituent(s) and optionally containing one or more heteroatoms selected from a sulfur atom, an oxygen atom and a nitrogen atom, R⁷ is an alkyl group or an alkyloxycarbonylalkyl group, provided that R⁶ is not 4-amino-5-chloro-2-methoxyphenyl group when Y is a single bond and one of the R³ and R⁴ is hydrogen atom and another is hydroxymethyl group, or a pharmaceutically acceptable salt thereof.

In the compounds [I] of the present invention, examples of the aryl (or heteroaryl) group in R¹ and R² include a 5- or 6-membered aryl group (or 5- to 10 membered heteroaryl group having one or more heteroatom(s) selected from sulfur atom, oxygen atom and nitrogen atom) such as a phenyl group, a thienyl group, a pyridyl group, a pyrazinyl group, a benzofuranyl group, a benzimidazolyl group, a quinolyl group, a thiazolyl group, a pyrimidinyl group, a benzothiazolyl group and the like. Said aryl (or heteroaryl) group may be substituted by the same or different one to three groups selected from (1) a halogen atom, (2) a cyano group, (3) an alkyl group optionally substituted by one to three groups selected from a halogen atom, a cycloalkyl group and an alkyloxy group, (4) an alkyloxy group optionally substituted by one to three groups selected from a halogen atom, an alkyloxy group and a mono- or di-alkylamino group, (5) an amino group optionally substituted by an alkyl group, an alkyloxyalkyl group, a cycloalkyl group and a mono- or dialkylamino-alkyl group, (6) a carbamoyloxy group optionally substituted by one to two alkyl groups, (7) an alkylsulfonyl group, (8) a cycloalkyloxy group, (9) a carbamoyl group optionally substituted by an alkyl group(s), (10) a nitro group, (11) an alkylthio group, (12) an aminosulfonyl group optionally substituted by an alkyl group(s), (13) an alkylsulfinyl group, (14) an alkyleneoxy group and (15) an alkylenedioxy group.

Examples of the saturated or unsaturated, 4- to 10-membered, nitrogen- or oxygen-containing heterocyclic group in R³ and R⁴ include a heterocyclic group such as a pyrrolidinyl group, a morpholinyl group, a pyridyl group and the like. Among them, preferred examples of such group include a saturated or unsaturated, 5- to 6-membered, nitrogen-containing heterocyclic group.

In case that the R⁶ is a straight or branched chain hydrocarbon group optionally having a substituent(s), examples of such group include a straight or branched chain C₁₋₁₂-hydrocarbon group optionally having a substituent(s). More concretely, the hydrocarbon group may be (1) a straight or branched chain C₁₋₁₂-alkyl group optionally having a substituent(s), (2) a straight or branched chain C₂₋₁₂-alkenyl group optionally having a substituent(s) or (3) a straight or branched chain C₂₋₁₂-alkynyl group optionally having a substituent(s).

In case that the R⁶ is a straight or branched chain hydrocarbon group having a substituent(s), such hydrocarbon groups include a hydrocarbon group having the same or different one to three substituents selected from the group consisting of: (1) a cycloalkyl group optionally fused to a benzene ring, (2) an amino group optionally substituted by the same or different one or two groups selected from an alkyl group, an alkyloxycarbonyl group, an alkylcarbonyl group, an arylalkyloxycarbonyl group, an alkylsulfonyl group, a morpholinocarbonyl group, a mono- or dialkyl-carbamoyl group, a mono- or di-alkylaminosulfonyl group, a halogenoalkylcarbonyl group and an alkyloxycarbonylcarbamoyl group, (3) an aryl (or biaryl) group optionally substituted by the same or different one to three groups selected from a halogen atom, a hydroxyl group, an alkyl group, an alkyloxy group, a trihalogenoalkyl group, a trihalogenoalkyloxy group, an alkyloxyalkyloxy group, a morpholinoalkyloxy group, an alkyloxycarbonyl group, a mono- or di-alkylamino group and an alkyloxycarbonylamino group, (4) a saturated or unsaturated, 3- to 14-membered, sulfur-, nitrogen- or oxygen-containing heterocyclic group optionally substituted by the same or different one to three groups selected from a halogen atom, an oxo group, an alkyl group, an alkyloxycarbonyl group, an arylalkyloxycarbonyl group, a trihalogeno-alkyl group, an alkylthio group and an aryl group, (5) a hydroxyl group, (6) an alkyloxy group optionally substituted by the same or different one to three groups selected from an alkyloxy group and aryl group, (7) an alkenyoxy group, (8) an aryloxy group optionally fused to a cycloalkyl ring and optionally substituted by the same or different one to three groups selected from a halogen atom, an alkyl group and a trihalogenoalkyloxy group, (9) a group of the formula: —SR_(a) in which R_(a) is an aryl group, an arylalkyl group or a saturated or unsaturated, 4- to 10-membered, nitrogen- or oxygen-containing heterocyclic group, (10) an alkyloxycarbonyl group, (11) an arylalkyloxycarbonyl group, (12) a cycloalkylcarbonyl group, (13) an arylcarbonyl group optionally substituted by the same or different one to three groups selected from a halogen atom and a trihalogenoalkyl group, (14) an arylsulfonyl group, and (15) a halogen atom.

In case that the substituent(s) in the straight or branched chain hydrocarbon group (R⁶) is a saturated or unsaturated, 3- to 14-membered, sulfur-, oxygen- or nitrogen-containing heterocyclic group or a group containing said heterocyclic group, such heterocyclic group may be selected from a group of the formula:

and said heterocyclic group may be further hydrogenated.

In case that R⁶ is an optionally substituted cyclic group, examples of such cyclic group include a group selected from (1) an optionally substituted, 6- to 14-membered, mono-, bi- or tri-cyclic aryl group, (2) an optionally substituted monocyclo-, bicyclo- or tri-cyclo-C₃₋₁₀ alkyl group (said cycloalkyl group being optionally fused to a benzene ring), and (3) a saturated or unsaturated, 3- to 14-membered, sulfur-, nitrogen- or oxygen-containing heterocyclic group optionally having a substituent and optionally forming a spiro-ring with a cycloalkyl ring.

In case that the cyclic group represented by R⁶ is an aryl group, such aryl group may be a phenyl group, a naphthyl group, a fluorenyl group and the like.

In case that the cyclic group represented by R⁶ is a monocyclo-, bicyclo- or tricyclo-alkyl group such monocyclo-, bicyclo- or tricyclo-alkyl group may be a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a tricyclo[2.2.1.0]heptyl group and the like.

In case that the cyclic group represented by R⁶ is a heterocyclic group, such heterocyclic group may be (1) a heteromonocyclic group selected from a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a pyrrolidinyl group, a pyrrolinyl group, a 3H-pyrrolinyl group, an imidazolidinyl group, an imidazolinyl group, a pyrrazolidinyl group, a pyrrazolinyl group, a thiazolidinyl group, a piperidyl group, a piperazinyl group, an azethidinyl group, an isothiazolyl group, an isoxazolyl group, a pyridyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, a thienyl group, a thiazolyl group, a furyl group, a pyranyl group and a morpholinyl group, (2) a heterobicyclic group selected from a 1H-indazolyl group, an indolizinyl group, an indolyl group, a 3H-indolyl group, an isoindolyl group, an indolinyl group, an isoindolinyl group, a purinyl group, a quinolyl group, a tetrahydroquinolyl group, an isoquinolyl group, a tetrahydroisoquinolyl group, a phthalazinyl group, a naphthyridinyl group, a quinoxalinyl group, a quinazolinyl group, a cinnolinyl group, a pteridinyl group, a pyrazolopyrimidinyl group, a chromanyl group, an isochromanyl group, a chromenyl group, a benzotriazolyl group, a 2H-benzotriazolyl group, a benzofuranyl group, an isobenzofuranyl group, a dihydrobenzofuranyl group, a phthalimido group, a benzothienyl group, a benzoxazolyl group, a benzoisoxazolyl group, a benzoxazinyl group, a benzimidazolyl group, a furopyridyl group and a group of the formula:

(3) a heterotricyclic group selected from a furonaphthyl group, a dihydrofuronaphthyl group, a carbazolyl group, a β-carbolinyl group and a group of the formula:

or (4) an oxaspirodecyl group.

Among the heterocyclic group mentioned above, a preferred example of the heterocyclic group may be a group of the formula:

and said heterocyclic group may be further hydrogenated.

In case that R⁶ is a substituted cyclic group, examples of such cyclic group include those substituted by the same or different one to four groups selected from the group consisting of (1) a halogen atom, (2) an oxo group, (3) a nitro group, (4) a cyano group, (5) an alkyl group optionally substituted by the same or different one to three groups selected from a halogen atom, an arylcarbonyl group, a mono-, di- or tri-halogeno-arylcarbonyl group, an aryl group, a hydroxyl group, a saturated or unsaturated, 4- to 10-membered, nitrogen- or oxygen-containing heterocyclic group optionally substituted by an oxo group, an alkyloxy group and an imino group, (6) an aminoalkyl group (the amino moiety of said group being optionally substituted by the same or different one to two groups selected from an alkyloxycarbonyl group, an arylcarbonyl group, an aryl-alkyloxy-carbonyl group, an alkyl group an alkyloxyalkyl group and a cycloalkyl group), (7) a cycloalkyl group, (8) an alkenyl group optionally substituted by an alkyloxy-carbonyl group, (9) an amino group optionally substituted by one to two groups selected from an alkyl group, an alkyloxycarbonyl group, an arylalkyloxycarbonyl group, an alkyloxyalkyl group and a halogenoalkylcarbonyl group, (10) an aryl group optionally substituted by the same or different one to three groups selected from a halogen atom and a saturated or unsaturated, 4- to 10-membered, nitrogen- or oxygen-containing heterocyclic group, (11) a saturated or unsaturated, 4- to 10-membered, nitrogen- or oxygen-containing heterocyclic group optionally substituted by the same or different one to three groups selected from a halogen atom, an oxo group and a saturated or unsaturated, 4- to 10-membered, nitrogen- or oxygen-containing heterocyclic group, (12) an alkyloxy group optionally substituted by the same or different one to three groups selected from a halogen atom, an alkyloxy group, an aryl group, a saturated or unsaturated, 4- to 10-membered, nitrogen- or oxygen-containing heterocyclic group and a mono- or di-alkylamino group, (13) a cycloalkyloxy group, (14) a cycloalkenyloxy group, (15) an aryloxy group, (16) an arylcarbonyl group optionally substituted by the same or different one to three halogen atom(s), (17) an alkylcarbonyl group, (18) an alkyloxycarbonyl group, (19) an arylalkyloxycarbonyl group, (20) a group of the formula: —SO₂R_(b) in which R_(b) is an alkyl group, an aryl group optionally substituted by one to three halogen atoms, an amino group optionally substituted by one to two alkyl groups or a saturated or unsaturated, 4- to 10-membered, nitrogen- or oxygen-containing heterocyclic group optionally substituted by the same or different one to three alkyl groups, (21) an alkynyl group optionally substituted by a group selected from a mono- or di-alkylamino group and a saturated or unsaturated, 4- to 10-membered, nitrogen- or oxygen-containing heterocyclic group, (22) an alkylthio group (the alkyl moiety of said group being optionally substituted by a group selected from a hydroxyl group and an alkyloxy group), (23) a carbamoyl group (the amino moiety of said group being optionally substituted by an alkyl group) and (24) a carbamoyloxy group optionally substituted by one or two alkyl groups.

In case that the substituent(s) in the straight or branched chain hydrocarbon group represented by R⁶ in the present compound [I] is an aryl group or an aryl-containing group, such aryl group may be a 6- to 14-membered, monocyclic-, bicyclic- or tricyclic-aryl group such as a phenyl group, a naphthyl group, a fluorenyl group and the like. Among them, preferred example may be a phenyl group. Besides, examples of the biaryl group include a biphenyl group.

In case that the substituent(s) in the straight or branched chain hydrocarbon group represented by R⁶ is a group containing a saturated or unsaturated, 4- to 10-membered, nitrogen- or oxygen-containing heterocyclic group, such 4- to 10-membered heterocyclic group may be a furyl group, a pyrrolidinyl group, a piperidinyl group, a morpholinyl group, a pyridyl group, a piperazinyl group, benzimidazolyl group and the like.

More specific examples of the compound [I] in the present invention include, for example, a compound in which:

(A) R¹ and R² are (a) the same or different and a phenyl group optionally substituted by one to three groups selected from a halogen atom, a C₁₋₆ alkyloxy group and a cyano group, or (b) both of the groups combine together with an adjacent CH group to form a group of the formula:

one of R³ and R⁴ is a hydrogen atom and another is a hydrogen atom or a hydroxyl group, R⁵ is a hydrogen atom or a C₁₋₆ alkyl group, Y is a single bond or —O—, and R⁶ is a straight or branched chain C₁₋₁₀ alkyl group optionally substituted by one to three groups selected from the group consisting of the following (i) to (xvii):

-   (i) a C₃₋₈ cycloalkyl group; (ii) a benzo-C₃₋₈ cycloalkyl     group; (iii) an amino group (said group being optionally substituted     by one or two groups selected from a C₁₋₆ alkyl group, a C₁₋₆     alkyloxy-carbonyl-carbamoyl group, a C₁₋₆ alkyloxy-carbonyl group, a     C₁₋₆ alkyl-carbonyl group, a trihalogeno-C₁₋₆ alkyl-carbonyl group,     a phenyl-C₁₋₆ alkyloxy-carbonyl group, a C₁₋₆ alkylsulfonyl group, a     morpholino-carbonyl group, a carbamoyl group substituted by one or     two C₁₋₆ alkyl groups and an aminosulfonyl group substituted by one     or two C₁₋₆ alkyl groups); (iv) an aryl group selected from a phenyl     group, a naphthyl group and a fluorenyl group (said aryl group being     optionally substituted by one to three groups selected from a     halogen atom, a hydroxyl group, a C₁₋₆ alkyl group, a C₁₋₆ alkyloxy     group, a trihalogeno-C₁₋₆ alkyl group, a trihalogeno-C₁₋₆ alkyloxy     group, a di(C₁₋₆ alkyl)amino group and a C₁₋₆ alkyloxy-carbonylamino     group); (v) a biphenyl group optionally substituted by a halogen     atom(s); (vi) a saturated or unsaturated, 5- to 14-membered sulfur-,     nitrogen- or oxygen-containing heterocyclic group (said heterocyclic     group being optionally substituted by one to two groups selected     from a halogen atom, an oxo group, a C₁₋₆ alkyl group, a C₁₋₆     alkyloxy-carbonyl group, a phenyl-C₁₋₆ alkyloxy-carbonyl group, a     trihalogeno-C₁₋₆ alkyl group, a C₁₋₆ alkylthio group and a phenyl     group); (vii) a hydroxyl group; (viii) a C₁₋₆ alkyloxy group (alkyl     moiety of said group being optionally substituted by one to two     groups selected from a C₁₋₆ alkyloxy group and a phenyl group); (ix)     a C₂₋₆ alkenyloxy group; (x) an aryloxy group selected from a     phenoxy group and a naphthyloxy group (aryl moiety of said group     being optionally substituted by one to two groups selected from a     halogen atom, a C₁₋₆ alkyl group and a trihalogeno-C₁₋₆ alkyloxy     group, and being optionally fused to a C₃₋₈ cycloalkyl ring); (xi) a     phenylthio group; (xii) a pyridylthio group; (xiii) a C₁₋₆     alkyloxy-carbonyl group (alkyl moiety of said group being optionally     substituted by a phenyl group); (xiv) a C₃₋₈ cycloalkyl-carbonyl     group; (xv) a benzoyl group; (xvi) a benzenesulfonyl group;     and (xvii) a halogen atom; or

(B) R¹ and R² are the same or different and a phenyl group optionally substituted by one to three halogen atoms, both R³ and R⁴ are a hydrogen atom, R⁵ is a hydrogen atom, Y is a single bond and R⁶ is a straight or branched chain C₂₋₆ alkenyl (or C₂₋₆ alkynyl) group optionally substituted by one or two groups selected from the group consisting of the following (i) to (iii):

-   (i) a phenyl group optionally-substituted by one to three groups     selected from a halogen atom, a C₁₋₆ alkyl group, a trihalogeno-C₁₋₆     alkyl group, a C₁₋₆ alkyloxy group, a C₁₋₆ alkyloxy-carbonyl group,     a C₁₋₆ alkyloxy-C₁₋₆ alkyloxy group and a morpholino-C₁₋₆ alkyloxy     group; (ii) a saturated or unsaturated 5- to 10-membered nitrogen-     or oxygen-containing heterocyclic group optionally substituted by a     halogen atom(s); and (iii) a phenyl-C₁₋₆ alkylthio group; or

(C) R¹ and R² are the same or different and (a) a phenyl group optionally substituted by one to three groups selected from a group consisting of the following (i) to (xvi):

-   (i) a halogen atom; (ii) a cyano group; (iii) a nitro group; (iv) a     C₁₋₆ alkyl group optionally substituted by one to three halogen     atoms; (v) a C₁₋₆ alkyloxy-C₁₋₆ alkyl group; (vi) a C₁₋₆ alkyloxy     group optionally substituted by one to three groups selected from a     halogen atom, a di(C₁₋₆ alkyl)amino group, a pyrrolidinyl group and     a morpholino group; (vii) a C₁₋₆ alkyloxy-C₁₋₆ alkyloxy     group; (viii) an amino group optionally substituted by one or two     groups selected from a C₁₋₆ alkyl group, a C₁₋₆ alkyloxy-C₁₋₆ alkyl     group, a C₃₋₈ cycloalkyl group and a di(C₁₋₆ alkyl)amino-C₁₋₆ alkyl     group; (ix) a di(C₁₋₆ alkyl)carbamoyl group; (x) a C₁₋₆ alkylthio     group; (xi) a C₁₋₃ alkyleneoxy group; (xii) a C₁₋₃ alkylenedioxy     group; (xiii) a di(C₁₋₆ alkyl)aminosulfonyl group; (xiv) a C₁₋₆     alkylsulfonyl group; (xv) a di(C₁₋₆ alkyl)carbamoyloxy group     and (xvi) a C₁₋₆ alkylsulfinyl group or (b) a sulfur-, oxygen- or     nitrogen-containing 5- to 10 membered monocyclic or bicyclic     heteroaryl group optionally substituted by one to three groups     selected from a halogen atom, a cyano group, a C₁₋₆ alkyl group     optionally substituted by one to three groups selected from a     halogen atom and a C₁₋₆ alkyloxy group, a di(C₁₋₆ alkyl)amino group,     a C₃₋₈ cycloalkyloxy group, and a C₁₋₆ alkyloxy group optionally     substituted by one to three groups selected from a halogen atom, a     C₁₋₆ alkyloxy group and a C₃₋₈ cycloalkyl group, -   one of R³ and R⁴ is (a) a hydrogen atom and another is a hydrogen     atom, a hydroxyl group, a carboxyl group, a hydroxy-C₁₋₆ alkyl     group, a C₁₋₆ alkyloxy group, a C₁₋₆ alkyloxy-C₁₋₆ alkyl group, a     C₁₋₆ alkyloxy-carbonyl group, a di(C₁₋₆ alkyl)amino-C₁₋₆ alkyl     group, a carbamoyl group (said group being optionally substituted by     one or two groups selected from a di(C₁₋₆ alkyl)amino-C₁₋₆ alkyl     group, a morpholino-C₁₋₆ alkyl group, a hydroxy-C₁₋₆ alkyl group, a     C₁₋₆ alkyl group, a halogeno-C₁₋₆ alkyl group and a pyridyl-C₁₋₆     alkyl group), a morpholino group or a pyrrolidinyl group or (b) R³     and R⁴ combine each other to form an oxo group, R⁵ is a hydrogen     atom or a C₁₋₆ alkyl group, Y is a single bond and R⁶ is a 6- to     11-membered mono-, bi- or tri-cyclic aryl group optionally     substituted by one to three groups selected from the group     consisting of the following (i) to (xxv): -   (i) a halogen atom; (ii) an oxo group; (iii) a nitro group; (iv) a     cyano group; (v) a C₁₋₆ alkyl group (said group being optionally     substituted by one to three groups selected from a halogen atom, a     hydroxyl group, a C₁₋₆ alkyloxy group, a phenyl group, a morpholino     group, a pyrrolidinyl group, an oxopyrrolidinyl group and a     benzimidazolyl group); (vi) an amino-C₁₋₆ alkyl group (amino moiety     of said group being optionally substituted by one or two groups     selected from a C₁₋₆ alkyl group, a C₁₋₆ alkyloxy-C₁₋₆ alkyl group,     a C₃₋₈ cycloalkyl group, a C₁₋₆ alkyloxy-carbonyl group and a     phenyl-C₁₋₆ alkyloxycarbonyl group); (vii) a C₃₋₈ cycloalkyl     group; (viii) a C₁₋₆ alkyloxy-carbonyl-C₂₋₆ alkenyl group; (ix) an     amino group (said group being optionally substituted by one or two     groups selected from a C₁₋₆ alkyl group, a C₁₋₆ alkyloxy-C₁₋₆ alkyl     group, a trihalogeno-C₁₋₆ alkyl-carbonyl group, a C₁₋₆     alkyloxy-carbonyl group and a phenyl-C₁₋₆ alkyloxycarbonyl     group); (x) a phenyl group; (xi) a heterocyclic group selected from     a pyrazolyl group, a pyrrolyl group, a piperidyl group and a     morpholino group (said heterocyclic group being optionally     substituted by one to three groups selected from a halogen atom, an     oxo group and a pyrimidinyl group); (xii) a C₁₋₈ alkyloxy group     (said group being optionally substituted by one to three groups     selected from a halogen atom, a C₁₋₆ alkyloxy group, a phenyl group,     a morpholino group and an amino group substituted by one or two C₁₋₆     alkyl groups), (xiii) a C₃₋₈ cycloalkyloxy group; (xiv) a C₃₋₈     cycloalkenyloxy group; (xv) a phenoxy group; (xvi) a benzoyl     group; (xvii) a C₁₋₆ alkyl-carbonyl group; (xviii) a C₁₋₆     alkyloxy-carbonyl group; (xix) an aminosulfonyl group optionally     substituted by one or two C₁₋₆ alkyl groups; (xx) a     piperazinylsulfonyl group optionally substituted by one to three     C₁₋₆ alkyl groups; (xxi) a C₂₋₆ alkynyl group optionally substituted     by one or two groups selected from an amino group substituted by one     or two C₁₋₆ alkyl groups and a pyrrolidinyl group; (xxii) a C₁₋₆     alkylthio group optionally substituted by a hydroxyl group; (xxiii)     a C₁₋₆ alkyloxy-C₁₋₆ alkylthio group; (xxiv) a carbamoyl group     optionally substituted by one or two C₁₋₆ alkyl groups; and (xxv) a     di(C₁₋₆ alkyl)carbamoyloxy group; or

(D) R¹ and R² are the same or different and a phenyl group optionally substituted by one to three halogen atoms, one of R³ and R⁴ is a hydrogen atom, another is a hydrogen atom or a C₁₋₆ alkyloxy group, R⁵ is a hydrogen atom, Y is a single bond and R⁶ is a C₃₋₁₀ mono- bi- or tri-cycloalkyl group (said cycloalkyl group being optionally fused to a benzene ring) optionally substituted by one to four groups selected from the group consisting of the following (i) to (vi):

-   (i) an oxo group; (ii) a C₁₋₆ alkyl group optionally substituted by     a halogenobenzoyl group; (iii) an amino-a C₁₋₆ alkyl group (amino     moiety of said group being optionally substituted by a C₁₋₆     alkyloxy-carbonyl group; (iv) an amino group optionally substituted     by a C₁₋₆ alkyloxy-carbonyl group; (v) a phenyl group optionally     substituted by one to three halogen atoms; and (vi) a benzoyl group     optionally substituted by one to three halogen atoms; or

(E) R¹ and R² are the same or different and (a) a phenyl group optionally substituted by one to three groups selected from a halogen atom, a cyano group, a C₁₋₆ alkyloxy group, a trifluoro-C₁₋₆ alkyl group, an amino group substituted by one or two groups selected from a C₁₋₆ alkyl group and a di(C₁₋₆ alkyl)carbamoyloxy group and a C₁₋₆ alkyloxy-C₁₋₆ alkyl group or (b) a sulfur-, oxygen- or nitrogen-containing 5- to 10-membered heteroaryl group optionally substituted by one to three groups selected from a C₁₋₆ alkyloxy group, a di(C₁₋₆ alkyl)amino group, a C₃₋₈ cycloalkyloxy group, a C₃₋₈ cycloalkyl-C₁₋₆ alkyloxy group and a trihalogeno-C₁₋₆ alkyloxy group, one of R³ and R⁴ is a hydrogen atom, another is a hydrogen atom or a C₁₋₆ alkyloxy group, R⁵ is a hydrogen atom, Y is a single bond and R⁶ is a saturated or unsaturated 3- to 14-membered, monocyclic- bicyclic- or tricyclic-heterocyclic group (said heterocyclic group optionally constituting a spiro-ring with a C₃₋₈ cycloalkyl group) optionally substituted by one to three groups selected from the group consisting of the following (i) to (xiv):

-   (i) an oxo group; (ii) a halogen atom; (iii) a cyano group; (iv) a     C₁₋₆ alkyl group (said group being optionally substituted by one to     three groups selected from a halogen atom, a C₁₋₆ alkyloxy group, an     imino group, a phenyl group and a pyrrolidinyl group); (v) an     amino-C₁₋₆ alkyl group (amino moiety of said group being optionally     substituted by one or two C₁₋₆ alkyl groups); (vi) an amino group     optionally substituted by one or two C₁₋₆ alkyl groups; (vii) a     phenyl group optionally substituted by one to three halogen     atoms; (viii) a heterocyclic group selected from a furyl group, a     pyridyl group and a pyrimidinyl group; (ix) a C₁₋₆ alkyloxy group     optionally substituted by one to three groups selected from halogen     atoms and a phenyl group; (x) a C₁₋₆ alkyl-carbonyl group; (xi) a     C₁₋₆ alkyloxy-carbonyl group; (xii) a C₁₋₆ alkylsulfonyl     group; (xiii) an aminosulfonyl group; (xiv) a benzenesulfonyl group     optionally substituted by one to three halogen atoms; and (xv) a     morpholinosulfonyl group; or

(F) R¹ and R² are the same or different and a phenyl group optionally substituted by one to three halogen atoms, both R³ and R⁴ are a hydrogen atom, R⁵ is a hydrogen atom, Y is a group of the formula: —NR⁷—, R⁶ is a C₁₋₆ alkyl group optionally substituted by a phenyl groups or a phenyl group optionally substituted by one to three halogen atoms and R⁷ is a C₁₋₆ alkyl group or a C₁₋₆ alkyloxy-carbonyl-C₁₋₆ alkyl group.

In case that the cyclic group represented by R⁶ in the compound [I] of the present invention is a substituted aryl group, preferred examples of such aryl group may be an aryl group substituted by the same or different one to three groups selected from an oxo group, a cyano group, a nitro group, a halogen atom, a C₁₋₆ alkyl group, a trifluoro-C₁₋₆ alkyl group, a diphenyl-C₁₋₆ alkyl group, a di(C₁₋₆ alkyl)amino-C₁₋₆ alkyl group, a phenyl-C₁₋₆ alkyl group, a pyrrolidinyl-C₁₋₆ alkyl group, a benzimidazolyl-C₁₋₆ alkyl group, a C₁₋₉ alkyloxy group, a di- or tri-fluoro-C₁₋₆ alkyloxy group, a phenoxy group, a phenyl-C₁₋₆ alkyloxy group, a C₁₋₆ alkyloxy-C₁₋₆ alkyloxy group, an aminosulfonyl group, a di(C₁₋₆ alkyl)aminosulfonyl group, a di(C₁₋₆ alkyl)amino group, a C₁₋₆ alkyloxy-carbonylamino group, a C₁₋₆ alkyloxy-carbonyl group, a phenyl-C₁₋₆ alkyloxycarbonyl-amino group, a C₁₋₆ alkyloxy-carbonyl-C₂₋₆ alkenyl group, a C₁₋₆ alkyl-carbonyl group, a C₁₋₆ alkylthio group, a-di(C₁₋₆ alkyl)carbamoyloxy group, a benzoyl group, a phenyl group, a C₃₋₈ cycloalkyl group, a C₃₋₈ cycloalkenyloxy group, a C₃₋₈ cycloalkyloxy group, a pyrrolyl group, an oxopyrrolidinyl group, a piperidyl group, a C₁₋₆ alkyl-piperazinyl-sulfonyl group, a pyrimidinyl-pyrazolyl group, a C₁₋₆ alkyloxy-carbonylamino-C₁₋₆ alkyl group, a phenyl-C₁₋₆ alkyloxy-carbonylamino-C₁₋₆ alkyl group, a di(C₁₋₆ alkyl)amino-C₂₋₆ alkynyl group, a N—(C₁₋₆ alkyloxy-C₁₋₆ alkyl)-N—(C₁₋₆ alkyl)amino-C₁₋₆ alkyl group, a N—(C₃₋₈ cycloalkyl)-N—(C₁₋₆ alkyl)amino-C₁₋₆ alkyl group, a N-(trifluoro-C₁₋₆ alkyl-carbonyl)-N—(C₁₋₆ alkyl)amino group, a pyrrolidinyl-C₂₋₆ alkynyl group, a C₁₋₆ alkyloxy-C₁₋₆ alkyl group, a hydroxy-C₁₋₆ alkyl group, a morpholino-C₁₋₆ alkyl group, a di(C₁₋₆ alkyl)amino-C₁₋₆ alkyloxy group, a morpholino-C₁₋₆ alkyloxy group, a C₁₋₆ alkylthio group, a C₁₋₆ alkyloxy-C₁₋₆ alkylthio group, a hydroxy-C₁₋₆ alkylthio group, a di(C₁₋₆ alkyl)carbamoyl group and a di(C₁₋₆ alkyl)carbamoyloxy group.

In case that the R⁶ is a substituted cycloalkyl group, preferred examples of such cycloalkyl group may be a mono-, bi- or tri-cycloalkyl group (said cycloalkyl group being optionally fused to a benzene ring) substituted by the same or different one to four groups selected from an oxo group, a C₁₋₆ alkyl group, a C₁₋₆ alkyloxy-carbonylamino-C₁₋₆ alkyl group, a halogenobenzoyl-C₁₋₆ alkyl group, a C₁₋₆ alkyloxy-carbonylamino group, a halogenobenzoyl group, a phenyl group and a halogenophenyl group.

In case that the R⁶ is a substituted heterocyclic group, preferred examples of such heterocyclic group may be a heterocyclic group substituted by the same or different one to three groups selected from an oxo group, a chlorine atom, a bromine atom, a cyano group, a C₁₋₆ alkyl group, a C₁₋₆ alkyloxy group, a diphenyl-C₁₋₆ alkyl group, C₁₋₆ alkyl-carbonyl group, a trifluoro-C₁₋₆ alkyl group, a trifluoro-C₁₋₆ alkyloxy group, a C₁₋₆ alkyloxycarbonyl group, a di(C₁₋₆ alkyl)amino-C₁₋₆ alkyl group, a di(C₁₋₆ alkyl)amino group, a phenyl group, a chlorophenyl group, a pyrrolidinyl-C₁₋₆ alkyl group, a pyridyl group, a pyrimidinyl group, a furyl group, a C₁₋₆ alkyl-sulfonyl group, an aminosulfonyl group, a morpholinosulfonyl group, a benzenesulfonyl group, a C₁₋₆ alkyloxy-imino-C₁₋₆ alkyl group, a chlorobenzenesulfonyl group, a benzyl group and a benzyloxy group.

Among the above-mentioned compounds [I] of the present invention, examples of the preferred compound may be those in which R¹ is a group of the formula:

R² is a group of the formula:

each of R¹¹ and R²¹ is independently a hydrogen atom, a cyano group, a halogen atom, a C₁₋₆ alkyloxy group optionally substituted by one to three groups selected from a halogen atom and a C₁₋₆ alkyloxy group, a C₁₋₆ alkyl group optionally substituted by one to three groups selected from a halogen atom and a C₁₋₆ alkyloxy group, a di(C₁₋₆ alkyl)carbamoyloxy group, a C₃₋₈ cycloalkyloxy group, a C₃₋₈ cycloalkyl-C₁₋₆ alkyloxy group, a C₁₋₆ alkylthio group, a di(C₁₋₆ alkyl)amino-C₁₋₆ alkyloxy group or a group of the formula: (R¹⁴)(R¹⁵)N—, each of R¹² and R²² is independently a hydrogen atom, a halogen atom or a morpholino-C₁₋₆ alkyloxy group, each of R¹³ and R²³ is independently a hydrogen atom or a halogen atom, R¹⁴ and R¹⁵ are the same or different and a hydrogen atom, a C₁₋₆ alkyl group, a C₁₋₆ alkyloxy-C₁₋₆ alkyl group, a C₃₋₈ cycloalkyl group or a di(C₁₋₆ alkyl)amino-C₁₋₆ alkyl group and Y is single bond.

Among them, examples of the more preferred compound may be those in which one of R³ and R⁴ in the formula [I] is a hydrogen atom, and the other is a hydrogen atom, a hydroxyl group, a C₁₋₆ alkyloxy group or morpholino group.

Among the compounds mentioned above, examples of the further preferred compounds include a compound of the formula [I-A]:

wherein Ring A is a group of the formula:

Ring B is a group of the formula:

one of Z¹ and Z² is a group of the formula: ═NH— and another is a group of the formula: ═CH— or ═N—, R^(11a) and R^(21a) are the same or different and (1) a hydrogen atom, (2) a halogen atom, (3) a cyano group, (4) a C₁₋₆ alkyloxy group optionally substituted by one to three groups selected from a halogen atom and a C₁₋₆ alkyloxy group, (5) a mono- or trifluoro-C₁₋₆ alkyl group, (6) a di(C₁₋₆ alkyl)carbamoyloxy group, (7) a C₁₋₆ alkylthio group, (8) an amino group substituted by a C₁₋₆ alkyl group and a C₁₋₆ alkyloxy-C₁₋₆ alkyl group, (9) a C₃₋₈ cycloalkyloxy group, (10) a C₃₋₈ cycloalkyl-C₁₋₆ alkyloxy group or (11) a C₁₋₆ alkyloxy-C₁₋₆ alkyl group, R^(13a) is a hydrogen atom or a halogen atom, R^(14a) is a C₁₋₆ alkyloxy group, R³¹ is a hydrogen atom, a hydroxyl group, a C₁₋₆ alkyloxy group or morpholino group, R⁶¹ is (1) a phenyl group substituted by one or two group(s) selected from a halogen atom, a trifluoro-C₁₋₆ alkyl group, a C₁₋₆ alkyloxy group, a trifluoro-C₁₋₆ alkyloxy group, a di(C₁₋₆ alkyl)carbamoyloxy group, a C₁₋₆ alkylthio group and a cyano group, (2) a pyridyl group substituted by one or two groups selected from a halogen atom and a cyano group or (3) a thienyl group substituted by a halogen atom or a trifluoro-C₁₋₆ alkyl group, or a pharmaceutically acceptable salt thereof.

Among the compounds [I] of the present invention, the most preferred one may be a compound selected from the group consisting of:

-   1-[bis-(4-chlorophenyl)methyl]-3-[[4-(trifluoromethoxy)benzoyl]amino]pyrrolidine; -   1-[bis-(4-chlorophenyl)methyl]-3-[(4-chlorobenzoyl)amino]pyrrolidine; -   1-[bis-(4-ethoxyphenyl)methyl]-3-[[4-(trifluoromethoxy)benzoyl]amino]pyrrolidine; -   1-[bis-(4-isopropoxyphenyl)methyl]-3-[[4-(trifluoromethoxy)benzoyl]amino]pyrrolidine; -   1-[bis-(4-chlorophenyl)methyl]-3-hydroxy-4-[[4-(trifluoromethoxy)benzoyl]amino]-pyrrolidine; -   1-[(4-chlorophenyl)[4-[N-methyl-N-(2-methoxyethyl)amino]phenyl]methyl]-3-[[4-(trifluoromethoxy)benzoyl]amino]pyrrolidine; -   1-[bis-(4-chlorophenyl)methyl]-3-methoxy-4-[[4-(trifluoromethoxy)benzoyl]amino]-pyrrolidine; -   1-[bis-(4-chlorophenyl)methyl]-3-methoxy-4-[(4-chlorobenzoyl)amino]pyrrolidine; -   1-[bis-(4-chlorophenyl)methyl]-3-ethoxy-4-[[4-(trifluoromethoxy)benzoyl]amino]-pyrrolidine; -   1-[bis-(4-chlorophenyl)methyl]-3-ethoxy-4-[(4-chlorobenzoyl)amino]pyrrolidine; -   1-[bis-(4-cyanophenyl)methyl]-3-[[4-(trifluoromethoxy)benzoyl]amino]pyrrolidine; -   1-[(2-chlorophenyl)(4-chlorophenyl)methyl]-3-[[4-(trifluoromethoxy)benzoyl]amino]-pyrrolidine; -   1-[bis-(4-chlorophenyl)methyl]-3-[(4-cyanobenzoyl)amino]pyrrolidine; -   1-[(4-chlorophenyl)(4-cyanophenyl)methyl]-3-[[4-(trifluoromethoxy)benzoyl]amino]-pyrrolidine; -   (3S,4S)-1-[bis-(4-chlorophenyl)methyl]-3-morpholino-4-[[4-(trifluoromethoxy)benzoyl]-amino]pyrrolidine; -   (3S,4S)-1-[bis-(4-chlorophenyl)methyl]-3-hydroxy-4-[(2-fluoro-4-cyanobenzoyl)amino]-pyrrolidine; -   (3R)-1-[(4-chlorophenyl)(4-cyanophenyl)methyl]-3-[[4-(trifluoromethyl)benzoyl]amino]-pyrrolidine; -   (3S,4S)-1-[bis-(4-chlorophenyl)methyl]-3-ethoxy-4-[(4-chlorobenzoyl)amino]pyrrolidine; -   (3S,4S)-1-[bis-(4-chlorophenyl)methyl]-3-methoxy-4-[(4-cyanobenzoyl)amino]-pyrrolidine; -   (3S,4S)-1-[bis-(4-chlorophenyl)methyl]-3-ethoxy-4-[(4-cyanobenzoyl)amino]pyrrolidine; -   (3S,4S)-1-[bis-(4-chlorophenyl)methyl]-3-ethoxy-4-[(2-fluoro-4-cyanobenzoyl)amino]-pyrrolidine; -   (3S,4S)-1-[bis-(4-chlorophenyl)methyl]-3-morpholino-4-[(4-chlorobenzoyl)amino]-pyrrolidine; -   (3R)-1-[(4-isopropyloxyphenyl)(4-cyanophenyl)methyl]-3-[[4-(trifluoromethoxy)-benzoyl]amino]pyrrolidine; -   (3S,4S)-1-[(4-chlorophenyl)(4-cyanophenyl)methyl]-3-methoxy-4-[[4-(trifluoro-methoxy)benzoyl]amino]pyrrolidine; -   (3S,4S)-1-[(4-chlorophenyl)(4-cyanophenyl)methyl]-3-methoxy-4-[[4-(trifluoromethyl)-benzoyl]amino]pyrrolidine; -   (3S,4S)-1-[(4-chlorophenyl)(4-cyanophenyl)methyl]-3-ethoxy-4-[(4-cyanobenzoyl)-amino]pyrrolidine; -   (3S,4S)-1-[(4-chlorophenyl)(4-cyanophenyl)methyl]-3-ethoxy-4-[[4-(trifluoromethoxy)-benzoyl]amino]pyrrolidine; -   (3S,4S)-1-[(4-chlorophenyl)(4-cyanophenyl)methyl]-3-ethoxy-4-[[4-(trifluoromethyl)-benzoyl]amino]pyrrolidine; -   (3S,4S)-1-[(4-chlorophenyl)(4-cyanophenyl)methyl]-3-ethoxy-4-[[3-fluoro-4-(trifluoro-methyl)benzolyl]amino]pyrrolidine; -   (3S,4S)-1-[(4-chlorophenyl)(4-cyanophenyl)methyl]-3-ethoxy-4-[(2-fluoro-4-cyano-benzoyl)amino]pyrrolidine; -   (3S,4S)-1-[(4-chlorophenyl)(4-cyanophenyl)methyl]-3-methoxy-4-[(2-fluoro-4-cyano-benzoyl)amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)[4-(trifluoromethyl)phenyl]methyl]-3-[[4-(trifluoromethoxy)-benzoyl]amino]pyrrolidine: -   (3R)-1-[[(S)-4-cyanophenyl](4-chlorophenyl)methyl]-3-[[4-(trifluoromethoxy)benzoyl]-amino]pyrrolidine: -   (3R)-1-[[(S)-4-cyanophenyl](4-chlorophenyl)methyl]-3-[[4-(trifluoromethyl)benzoyl]-amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(6-methoxypyridin-3-yl)methyl]-3-[[4-(trifluoromethoxy)-benzoyl]amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(6-methoxypyridin-3-yl)methyl]-3-[[4-(trifluoromethyl)benzoyl]amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(4-isopropyloxyphenyl)methyl]-3-[[4-(trifluoromethyl)benzoyl]-amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(4-isopropyloxyphenyl)methyl]-3-[(4-cyanobenzoyl)amino]-pyrrolidine; -   (3R)-1-[(4-cyanophenyl)[2-fluoro-4-(trifluoromethyl)phenyl)]methyl]-3-[(4-cyano-benzoyl)amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(4-isopropyloxyphenyl)methyl]-3-[(4-chlorobenzoyl)amino]-pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(4-ethoxyphenyl)methyl]-3-[(4-cyanobenzoyl)amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(4-ethoxyphenyl)methyl]-3-[[4-(trifluoromethoxy)benzoyl]-amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(4-ethoxyphenyl)methyl]-3-[[4-(trifluoromethyl)benzoyl]amino]-pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(4-ethoxyphenyl)methyl]-3-[(4-chlorobenzoyl)amino]-pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(6-isopropyloxypyridin-3-yl)methyl]-3-[(4-cyanobenzoyl)amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(6-isopropyloxypyridin-3-yl)methyl]-3-[[4-(trifluoromethoxy)-benzoyl]amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(6-isopropyloxypyridin-3-yl)methyl]-3-[[4-(trifluoromethyl)-benzoyl]amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(6-isopropyloxypyridin-3-yl)methyl]-3-[(4-chlorobenzoyl)-amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)[4-(trifluoromethoxy)phenyl]methyl]-3-[(4-cyanobenzoyl)-amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)[4-(trifluoromethoxy)phenyl]methyl]-3-[(4-chlorobenzoyl)-amino]pyrrolidine; -   (3R)-1-[(4-chlorophenyl)[4-(trifluoromethoxy)phenyl]methyl]-3-[(4-cyanobenzoyl)-amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)[4-(trifluoromethoxy)phenyl]methyl]-3-[[4-(trifluoromethyl)-benzoyl]amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(4-chloro-2-fluorophenyl)]methyl]-3-[[4-(trifluoromethyl)-benzoyl]amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(4-chlorophenyl)methyl]-3-[[5-(trifluoromethyl)-2-thenoyl]-amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(4-methylthiophenyl)methyl]-3-[(4-cyanobenzoyl)amino]-pyrrolidine; -   (3R)-1-[(S)-(4-cyanophenyl)[4-(trifluoromethyl)phenyl]methyl]-3-[(4-cyanobenzoyl)-amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)[4-(trifluoromethyl)phenyl]methyl]-3-[(2-fluoro-4-cyano-benzoyl)amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(6-isopropyloxypyridin-3-yl)methyl]-3-[(2-fluoro-4-cyano-benzoyl)amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(4-ethoxyphenyl)methyl]-3-[(2-fluoro-4-cyanobenzoyl)amino]-pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(4-isopropyloxyphenyl)methyl]-3-[(2-fluoro-4-cyanobenzoyl)-amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(6-ethoxypyridin-3-yl)methyl]-3-[(2-fluoro-4-cyanobenzoyl)-amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)[6-(2,2-difluoroethoxy)-pyridin-3-yl]methyl]-3-[(2-fluoro-4-cyanobenzoyl)amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(6-ethoxypyridin-3-yl)methyl]-3-[(4-cyanobenzoyl)amino]-pyrrolidine; -   (3R)-1-[(4-cyanophenyl)[6-(2,2-difluoroethoxy)pyridin-3-yl]methyl]-3-[(4-cyanobenzoyl)amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)[6-(2-methoxyethoxy)-pyridin-3-yl]methyl]-3-[(4-cyanobenzoyl)amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(2-isopropyloxypyrimidin-5-yl)methyl]-3-[(4-cyanobenzoyl)-amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(4-fluoromethylphenyl)methyl]-3-[(4-cyanobenzoyl)amino]-pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(4-fluoromethylphenyl)methyl]-3-[(4-cyano-2-fluorobenzoyl)-amino]pyrrolidine; -   (3R)-1-[(4-chlorophenyl)(2-isopropyloxypyrimidin-5-yl)methyl]-3-[(4-cyanobenzoyl)-amino]pyrrolidine; -   (3R)-1-[(4-chlorophenyl)(2-isopropyloxypyrimidin-5-yl)methyl]-3-[(4-cyano-2-fluoro-benzoyl)amino]pyrrolidine; -   (3R)-1-[(2-isopropyloxypyrimidin-5-yl)[4-(trifluoromethyl)phenyl]methyl]-3-[(4-cyano-benzoyl)amino]pyrrolidine; -   (3R)-1-[(2-isopropyloxypyrimidin-5-yl)[4-(trifluoromethyl)phenyl]methyl]-3-[(4-cyano-2-fluorobenzoyl)amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(2-isopropyloxypyrimidin-5-yl)methyl]-3-[(4-cyano-2-fluoro-benzoyl)amino]pyrrolidine; -   (3R)-1-[(6-isopropyloxymethylpyridin-3-yl)[4-(trifluoromethyl)phenyl]methyl]-3-[(4-cyanobenzoyl)amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(2-ethoxythiazol-5-yl)methyl]-3-[(4-cyanobenzoyl)amino]-pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(2-isopropyloxythiazol-5-yl)methyl]-3-[(6-cyanonicotinoyl)-amino]pyrrolidine; -   (3R)-1-[(4-chlorophenyl)(6-methoxymethylpyridin-3-yl)methyl]-3-[(4-cyanobenzoyl)-amino]pyrrolidine; -   (3R)-1-[(6-methoxymethylpyridin-3-yl)[4-(trifluoromethyl)phenyl]methyl]-3-[(4-cyano-benzoyl)amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(6-methoxymethylpyridin-3-yl)methyl]-3-[(4-cyanobenzoyl)-amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)[6-(2-fluoroethoxy)pyridin-3-yl]methyl]-3-[(4-cyanobenzoyl)-amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(4-fluoromethylphenyl)methyl]-3-[(4-ethoxybenzoyl)amino]-pyrrolidine; -   (3R)-1-[(4-cyanophenyl)[4-(trifluoromethyl)phenyl]methyl]-3-[(4-methylthiobenzoyl)-amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)[4-(trifluoromethyl)phenyl]methyl]-3-[(5-bromo-2-thenoyl)-amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(2-isopropyloxythiazol-5-yl)methyl]-3-[(4-cyano-2-fluoro-benzoyl)amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(2-isopropyloxythiazol-5-yl)methyl]-3-[(4-cyanobenzoyl)-amino]pyrrolidine; -   (3R)-1-[(4-methoxyphenyl)(6-isopropyloxypyridin-3-yl)methyl]-3-[(4-cyanobenzoyl)-amino]pyrrolidine; -   (3R)-1-[(4-methoxyphenyl)(6-isopropyloxypyridin-3-yl)methyl]-3-[(4-cyano-2-fluoro-benzoyl)amino]pyrrolidine; -   (3R)-1-[(4-methoxyphenyl)(6-isopropyloxypyridin-3-yl)methyl]-3-[[(6-cyanopyridin-3-yl)carbonyl]amino]pyrrolidine; -   (3R)-1-[(4-ethoxyphenyl)(6-isopropyloxypyridin-3-yl)methyl]-3-[(4-cyanobenzoyl)-amino]pyrrolidine; -   (3R)-1-[(4-ethoxyphenyl)(6-isopropyloxypyridin-3-yl)methyl]-3-[(4-cyano-2-fluoro-benzoyl)amino]pyrrolidine; -   (3R)-1-[(4-ethoxyphenyl)(6-isopropyloxypyridin-3-yl)methyl]-3-[[(6-cyanopyridin-3-yl)-carbonyl]amino]pyrrolidine; -   (3R)-1-[(4-isopropyloxyphenyl)(6-isopropyloxypyridin-3-yl)methyl]-3-[(4-cyano-benzoyl)amino]pyrrolidine; -   (3R)-1-[(4-isopropyloxyphenyl)(6-isopropyloxypyridin-3-yl)methyl]-3-[(4-cyano-2-fluorobenzoyl)amino]pyrrolidine; -   (3R)-1-[(4-isopropyloxyphenyl)(6-isopropyloxypyridin-3-yl)methyl]-3-[[(6-cyano-pyridin-3-yl)carbonyl]amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]methyl]-3-[(4-cyano-benzoyl)amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]methyl]-3-[(4-cyano-2-fluorobenzoyl)amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]methyl]-3-[[(6-cyano-pyridin-3-yl)carbonyl]amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(2-ethoxypyrimidin-5-yl)methyl]-3-[(4-cyanobenzoyl)amino]-pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(2-ethoxypyrimidin-5-yl)methyl]-3-[(4-cyano-2-fluorobenzoyl)-amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)[6-(1-fluoromethyl-2-fluoroethoxy)pyridin-3-yl]methyl]-3-[(4-cyanobenzoyl)amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(6-isopropyloxypyridin-3-yl)methyl]-3-[(4-dimethylamino-carbonyloxybenzoyl)amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)[4-(trifluoromethyl)phenyl]methyl]-3-[(4-dimethylamino-carbonyloxybenzoyl)amino]pyrrolidine; -   (3R)-1-[bis-(6-isopropyloxypyridin-3-yl)methyl]-3-[(4-cyanobenzoyl)amino]pyrrolidine; -   (3R)-1[(4-cyanophenyl)(2-ethoxythiazol-5-yl)methyl]-3-[(4-cyano-2-fluorobenzoyl)-amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(2-ethoxythiazol-5-yl)methyl]-3-[[(6-cyanopyridin-3-yl)-carbonyl]amino]pyrrolidine; -   (3R)-1-[bis-(6-isopropyloxypyridin-3-yl)methyl]-3-[(4-cyano-2-fluorobenzoyl)amino]-pyrrolidine; -   (3R)-1-[bis-(6-isopropyloxypyridin-3-yl)methyl]-3-[[(6-cyanopyridin-3-yl)carbonyl]-amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(4-dimethylaminocarbonyloxyphenyl)methyl]-3-[(4-cyano-benzoyl)amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(4-dimethylaminocarboliyloxyphenyl)methyl]-3-[(4-cyano-2-fluorobenzoyl)amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(4-dimethylaminocarbonyloxyphenyl)methyl]-3-[[(6-cyano-pyridin-3-yl)carbonyl]amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(2-dimethylaminopyrimidin-5-yl)methyl]-3-[(4-cyanobenzoyl)-amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(2-dimethylaminopyrimidin-5-yl)methyl]-3-[(4-cyano-2-fluoro-benzoyl)amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(2-dimethylaminopyrimidin-5-yl)methyl]-3-[[(6-cyanopyridin-3-yl)carbonyl]amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(2-diethylaminopyrimidin-5-yl)methyl]-3-[(4-cyanobenzoyl)-amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(2-diethylaminopyrimidin-5-yl)methyl]-3-[(4-cyano-2-fluoro-benzoyl)amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(2-diethylaminopyrimidin-5-yl)methyl]-3-[[(6-cyanopyridin-3-yl)carbonyl]amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)[4-[N-(2-methoxyethyl)-N-methylaminophenyl]]methyl]-3-[[(6-cyanopyridin-3-yl)carbonyl]amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)[4-(N-isopropyl-N-methylamino)phenyl]methyl]-3-[(4-cyano-benzoyl)amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)[4-(N-ethyl-N-methylamino)phenyl]methyl]-3-[(4-cyano-benzoyl)amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)[4-[N-(2-methoxyethyl)-N-methylaminophenyl]]methyl]-3-[(4-cyano-2-fluorobenzoyl)amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)[4-(N-isopropyl-N-methylamino)phenyl]methyl]-3-[(4-cyano-2-fluorobenzoyl)amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)[4-(N-ethyl-N-methylamino)phenyl]methyl]-3-[(4-cyano-2-fluorobenzoyl)amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)[4-(N-methyl-N-n-propylamino)phenyl]methyl]-3-[(4-cyano-benzoyl)amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)[4-(N-methyl-N-n-propylamino)phenyl]methyl]-3-[(4-cyano-2-fluorobenzoyl)amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)[4-[N-(2-methoxyethyl)-N-methylaminophenyl]]methyl]-3-[[(6-cyanopyridin-3-yl)carbonyl]amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)[4-(N-isopropyl-N-methylamino)phenyl]methyl]-3-[[(6-cyano-pyridin-3-yl)carbonyl]amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)[4-(N-ethyl-N-methylamino)phenyl]methyl]-3-[[(6-cyano-pyridin-3-yl)carbonyl]amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)[4-(N-methyl-N-n-propylamino)phenyl]methyl]-3-[[(6-cyano-pyridin-3-yl)carbonyl]amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(6-cyclobutyloxypyridin-3-yl)methyl]-3-[(4-cyanobenzoyl)-amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(6-cyclobutyloxypyridin-3-yl)methyl]-3-[(4-cyano-2-fluoro-benzoyl)amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(6-cyclobutyloxypyridin-3-yl)methyl]-3-[[(6-cyanopyridin-3-yl)-carbonyl]amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(6-cyclopentyloxypyridin-3-yl)methyl]-3-[(4-cyanobenzoyl)-amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(6-cyclopentyloxypyridin-3-yl)methyl]-3-[(4-cyano-2-fluoro-benzoyl)amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(6-cyclopentyloxypyridin-3-yl)methyl]-3-[[(6-cyanopyridin-3-yl)carbonyl]amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(6-cyclopropylmethoxypyridin-3-yl)methyl]-3-[(4-cyano-benzoyl)amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(6-cyclopropylmethoxypyridin-3-yl)methyl]-3-[(4-cyano-2-fluorobenzoyl)amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)(6-cyclopropylmethoxypyridin-3-yl)methyl]-3-[[(6-cyano-pyridin-3-yl)carbonyl]amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)[6-(3-pentyloxy)pyridin-3-yl]methyl]-3-[(4-cyanobenzoyl)-amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)[6-(3-pentyloxy)pyridin-3-yl]methyl]-3-[(4-cyano-2-fluoro-benzoyl)amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)[6-(3-pentyloxy)pyridin-3-yl]methyl]-3-[[(6-cyanopyridin-3-yl)-carbonyl]amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]methyl]-3-[(4-cyano-benzoyl)amino]pyrrolidine; -   (3R)-1-[(4-cyanophenyl)[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]methyl]-3-[(4-cyano-2-fluorobenzoyl)amino]pyrrolidine;     and -   (3R)-1-[(4-cyanophenyl)[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]methyl]-3-[[(6-cyano-pyridin-3-yl)carbonyl]amino]pyrrolidine;     or     a pharmaceutically acceptable salt thereof.

When the compound [I] of the present invention has an asymmetric carbon atom(s) in its molecule, it may exist in the form of a stereoisomer thereof (diastereoisomers, optical isomers) owing to said asymmetric carbon atom(s) thereof, and the present invention also includes one of the stereoisomers and a mixture thereof.

A compound [I] of the present invention shows a potent antagonistic activity against CB1 receptor and may be useful as: (i) an agent for prevention and/or treatment of a CB1 receptor-mediated diseases such as psychosis including schizophrenia, anxiety disorders, stress, depression, epilepsy, neurodegenerative disorders, spinocerebellar disorders, cognitive disorders, craniocerebral trauma, panic attack, peripheral neuropathy, glaucoma, migraine, Parkinson's disease, Alzheimer's disease, Huntington's disease, Raynaud's syndrome, tremor, obsessive-compulsive disorders, amnesia, geriatric dementia, thymic disorders, Tourette's syndrome, tardive dyskinesia, bipolar disorders, cancer, drug-induced dyskinesia, dystonia, septic shock, hemorrhagic shock, hypotension, insomnia, immunological diseases including inflammations, multiple screlosis, emesis, diarrhea, asthma, appetite disorders such as bulimarexia and the like, obesity, non insulin-dependent diabetes mellitus (NIDDM), memory disorders, urinary disorders, cardiovascular disorders, infertility disorders, infections, demyelination-related diseases, neuroinflammation, viral encephalitis, cerebral vascular incidents, cirrhosis of the liver or intestinal transit disorders; (ii) an agent for withdrawal from a chronic treatment, alcohol dependence or drug abuse (e.g., an opioid, barbiturate, marijuana, cocaine, amphetamine, phencyclidine, a hallucinogenic agent, a benzodiazepine compound and the like); (iii) an agent for enhancing analgesic activity of analgesic or narcotic drugs and the like; or (iv) an agent for smoking cessation (withdrawal from smoking or nicotine dependence).

In addition, the compound [I] of the present invention shows a low toxicity and is safe as medicaments.

The compound [I] of the present invention can be clinically used either in the free form or in the form of a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable salt of the compound [I] includes a salt with an inorganic acid such as hydrochloride, sulfate, phosphate or hydrobromide, or a salt with an organic acid such as acetate, fumarate, oxalate, citrate, methanesulfonate, benzenesulfonate, tosylate or maleate. Besides, when the compound [I] of the present invention has a carboxyl group(s) and the like in its molecule, examples of the pharmaceutically acceptable salt include, salts with a base such as alkaline metal (e.g., sodium salt, potassium salt) or alkaline earth metal (e.g., calcium salt).

The compound [I] or a pharmaceutically acceptable salt thereof includes either intramolecular salt or an additive thereof, and solvates or hydrates thereof.

The present compound [I] or a pharmaceutically acceptable salt thereof can be either orally or parenterally, and can be formulated into a conventional pharmaceutical preparation such as tablets, granules, capsules, powders, injections or inhalants.

The dose of the compound [I] of the present invention or a pharmaceutically acceptable salt thereof may vary in accordance with the administration routes, and the ages, weights and conditions of the patients. For example, when administered in an injection preparation, it is usually in the range of about 0.0001 to 1.0 mg/kg/day, preferably in the range of about 0.001 to 0.1 mg/kg/day. When administered in an oral preparation, it is usually in the range of about 0.001 to 100 mg/kg/day, preferably in the range of 0.01 to 10 mg/kg/day.

The compound [I] of the present invention can be prepared by the following methods but should not be construed to be limited thereto.

(Method A)

According to the present invention, a compound [I] can be prepared by reacting a compound of the formula [II]:

wherein the symbols are the same as defined above with a compound of the formula [III]: R⁶—Y—COOR⁰  [III] wherein R⁰ is a hydrogen atom, an alkyl group or a benzyl group and other symbols are the same as defined above or a salt thereof.

When R⁰ is a hydrogen atom, the above-mentioned reaction can be carried out in a solvent in the presence of a condensing agent, and in the presence or absence of an activating agent and a base. Examples of the solvent include any solvent which does not disturb the reaction, such as methylene chloride, chloroform, dimethylformaide, dimethylacetamide, tetrahydrofuran, dioxane, toluene, benzene, 1,2-dichloroethane, 1-methyl-pyrrolidinone, 1,2-dimethoxyethane and the like.

The condensing agent may be, for example, dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC HCl), diphenyl-phosphoryl azide (DPPA), carbonyldiimidazole (CDI), diethylcyanophosphonate (DEPC), diisopropylcarbodiimide (DIPCI), benzotriazol-1-yloxytrispyrrolidinophosphonium hexafluorophosphate (PyBOP), carbonylditriazole, N-cyclohexylcarbodiimide-N′-propyloxymethylpolystyrene (PS-carbodiimide), N-ethoxycarbonyl-2-ethoxy-1,2-dihydro quinoline (EEDQ), 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluoro-phosphate (HATU), 2-(1H-benzotriazol-1-yl-1,1,3,3-tetramethyluronium hexafluoro-phosphate (HBTU), bromotrispyrrolidinophosphonium hexafluorophosphate (PyBroP), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), chloro-1,1,3,3-tetramethyluronium hexachloroantimonate (ACTU) and the like.

Examples of the activating agent include 1-hydroxybenzotriazole (HOBt), 1-hydroxysuccinimide (HOSu), dimethylaminopyridine (DMAP), 1-hydroxy-7-azabenzotriazole (HOAt), hydroxyphthalimide (HOPht), pentafluorophenol (Pfp-OH), 1-hydroxybenzotriazole-6-sulfonamidomethylpolystyrene (PS-HOBt) and the like.

The base includes, for example, pyridine, triethylamine, diisopropylethylamine, 4-methylmorpholine, 1,8-diazabicyclo[5,4,0]-7-undecene (DBU) and the like.

In the above-mentioned process, the compound [II] can be used in an amount of 0.33 to 1.5 moles, preferably 0.5 to 1.0 moles per one mole of the compound [III]. The condensing agent can be used in an amount of 1.0 to 3.0 moles, preferably 1.0 to 1.2 moles per one mole of the compound [II] or [III]. The base can be used in an amount of 1.0 to 3.0 moles, preferably 1.0 to 1.2 moles per one mole of the compound [II] or [III]. The activating agent can be used in an amount of 0.1 to 2.0 moles, preferably 0.2 to 1.0 moles per one mole of the compound [II] or [III]. The reaction can be carried out at 0 to 150° C., preferably 20 to 80° C.

When R⁰ in the compound [III] is hydrogen atom, the reaction process A can be carried out by converting the compound [III] to a reactive derivative at the carboxyl group and the like (e.g., an acid halide, a mixed acid anhydride) and reacting the reactive derivative with the compound [II] in the presence of the base in or without the solvent.

When R⁰ in the compound [III] is a lower alkyl group or a benzyl group, the reaction process A can be also carried out by converting the compound [III] to a corresponding carboxylic acid compound by a conventional manner such as hydrolysis, acidolysis using hydrochloric acid, formic acid, trifluoroacetic acid and the like or hydrogenation and then reacting the carboxylic acid compound with the compound [II] by the above-mentioned manner.

(Method B)

According to the present invention, a compound [I] can be prepared by reacting a compound of the formula [IV]:

wherein X is a reactive residue and other symbols are the same as defined above with a compound of the formula [V]:

wherein the symbols are the same as defined above.

The above-mentioned reaction can be carried out in a solvent in the presence of a base and in the presence or absence of an additive. Examples of the solvent include any solvent which does not disturb the reaction, such as tetrahydrofuran, dimethylformaide, dimethylacetamide, dimethylsulfoxide, ethanol, isopropyl alcohol, acetonitrile, 1,4-dioxane, 1,3-dimethyl-2-imidazolidinone and the like. The base includes potassium carbonate, sodium carbonate, triethylamine, diisopropylethylamine, pyridine, sodium hydroxide, potassium hydroxide and the like. The additive includes sodium iodide, copper(I) iodide, copper(II) iodide, copper powder, potassium iodide, a tetraalkylammonium halide (e.g., tetrabutylammonium chloride, tetraethyl-ammonium chloride) and the like.

The reactive residue represented by X may be a halogen atom such as fluorine atom, chlorine atom, bromine atom or iodine atom, trifluoromethanesulfonyloxy group, p-toluenesulfonyloxy group, methanesulfonyloxy group, hydroxyl group and the like.

When X is hydroxyl group, Mitsunobu reagents such as triphenylphosphinediethylazodicarboxylate, triphenylphosphinediisopropyl azodicarboxylate and the like can be used in the present reaction.

In the above-mentioned process, the compound [IV] can be used in an amount of 0.33 to 3.0 moles, preferably 0.66 to 1.5 moles per one mole of the compound [V]. The base can be used in an amount of 1.0 to 3.0 moles, preferably 1.0 to 1.2 moles per one mole of the compound [IV] or [V]. The additive can be used in an amount of 0.1 to 2.0 moles, preferably 0.2 to 1.0 moles per one mole of the compound [IV] or [V]. The reaction can be carried out at 50 to 150° C., preferably 80 to 120° C.

(Method C)

Among the compounds [I] of the present invention, a compound of the formula [I-a]:

wherein each of R⁸ and R⁹ is independently a group selected from an alkyl group, an arylalkyl group, an alkyloxycarbonylalkyl group and an aryl group optionally substituted by a halogen atom, or both of the groups combine each other together with an adjacent nitrogen atom to form a heterocyclic group (said heterocyclic group being optionally fused to a benzene ring and optionally substituted by a halogenoaryl group), and other symbols are the same as defined above can be also prepared by reacting a compound [II] with a compound of the formula [VI]: (R⁸)(R⁹)NH  [VI] wherein the symbols are the same as defined above in the presence of a compound of the formula [VII]:

wherein W¹ and W² are the same or different and a removing group.

In the compound [VII], examples of W¹ and W² include an imidazolyl group, a halogen atom or a phenoxy group. Concrete examples of such compound include 1,1′-carbonyldiimidazole, phosgene, triphosgene and the like.

Examples of the solvent include any solvent which does not disturb the reaction, such as acetonitrile, dichloromethane, tetrahydrofuran and the like.

In the above-mentioned process, the compound [II] can be used in an amount of 0.33 to 2.0 moles, preferably 0.66 to 1.0 moles per one mole of the compound [VI]. The compound [VII] can be used in an amount of 1.0 to 3.0 moles, preferably 1.0 to 1.2 moles per one mole of the compound [II] or [VI]. The reaction can be carried out at 0 to 150° C., preferably 20 to 80° C.

Moreover, the compound [I-a] can be prepared by: a) reacting the compound [II] with the compound [VII] to obtain a compound of the formula [VIII]:

wherein the symbols are the same as defined above and, if necessary, after converting the product to its reactive derivative, reacting the product with the compound [VI], or b) reacting the compound [VI] with the compound [VII] to obtain a compound of the formula [IX]:

wherein the symbols are the same as defined above and, if required, after converting the product to its reactive derivative, reacting the product with the compound [II].

Examples of the reactive derivative of the compound [VIII] or [IX] include those in which W² is converted to a group of the formula:

and such reactive derivative can be obtained by reacting the compound [IX] in which a group corresponding to W² is an imidazolyl group with methyl iodide.

The reaction of the compound [II] or the compound [IV] with the compound [VII] can be carried out at 0 to 150° C., preferably at 20 to 80° C. The compound [VII] can be used in an amount of 1.0 to 3.0 moles, preferably 1.0 to 1.2 moles per one mole of the compound [II] or [VI]. The compound [VII] can be used in an amount of 1.0 to 3.0 moles, preferably 1.0 to 1.2 moles per one mole of the compound [II] or [VI]. Examples of the solvent include any solvent which does not disturb the reaction, such as acetonitrile, dichloromethane, tetrahydrofuran and the like.

The reaction to convert the compound [VIII] or [IX] to its reactive derivative can be carried out by treating such compound with methyl iodide at 0 to 150° C., preferably at 40 to 80° C. The compound [VII] can be used in an amount of 1.0 to 3.0 moles, preferably 1.0 to 1.2 moles per one mole of the compound [VIII] or [IX]. Examples of the solvent include any solvent which does not disturb the reaction, such as acetonitrile, dichloromethane, tetrahydrofuran and the like.

The reaction of the compound [VIII] (or its reactive derivative) with the compound [VI] or the reaction of the compound [IX] (or its reactive derivative) with the compound [II] can be conducted in the presence of a base at 0 to 150° C., preferably at 20 to 80° C. Such reactive derivative can be used in an amount of 0.33 to 3.0 moles, preferably 0.66 to 1.5 moles per one mole of the compound [VI] or [II]. Examples of the base include triethylamine and the like. Examples of the solvent include any solvent which does not disturb the reaction, such as acetonitrile, dichloromethane, tetrahydrofuran and the like.

The objective compound [I] of the present invention can be also prepared by intramolecularly converting the substituent(s) in R¹, R² and/or R⁶, or the group R³ and/or R⁴ of the compound [I] as obtained above to the other desired substituent(s) or the other groups within the scope the present invention. The intramolecular conversion processes can be selected according to the kinds of the objective substituents or groups, and may be carried out, for example, in the following methods (a) to (k).

Method (a): A compound [I] in which the substituent(s) in R¹ and/or R² is cyano group can be obtained by reacting a corresponding compound [I] in which the substituent(s) in R¹ and/or R² is a halogen atom with zinc cyanide in the presence of a catalyst and an additive. Examples of said catalyst include a palladium catalyst such as palladium(II) acetate, tris(dibenzylideneacetone)dipalladium(0), trans-dichlorobis-(tricyclohexylphosphine)palladium(II), tetrakis(triphenylphosphine)palladium(0) and the like. Examples of the additive include a phosphine compound such as 1,1′-bis-(diphenylphosphino)ferrocene, racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 2-(di-tert-butylphosphino)biphenyl, 2-(dicyclohexylphosphino)biphenyl, 2-dicyclohexyl-phosphino-2′-(N,N′-dimethylamino)biphenyl, tri-tert-butylphospine and the like.

Method (b): A compound [I] in which the substituent(s) in R¹ and/or R² is an alkylamino group or a cycloalkylamino group can be obtained by reacting a corresponding compound [I] in which the substituent(s) in R¹ and/or R² is a halogen atom with a mono- or di-alkylamine or a cycloalkylamine in the presence of a catalyst, an additive and a base. Examples of the catalyst and the additive may be the palladium compounds and the phosphine compounds exemplified in Method (a), respectively. Examples of the base include potassium carbonate, cesium carbonate and the like.

Method (c): A compound [I] in which R³ and R⁴ combine each other to form an oxo group can be obtained by oxidizing a corresponding compound [I] in which one of the R³ and R⁴ is a hydrogen atom and another is a hydroxyl group. The oxidation can be carried out in a solvent in the presence of an oxidizing agent such as activated dimethylsulfoxide and the like. Dimethylsulfoxide can be activated by oxalyl chloride, dicyclohexylcarbodiimide, trifluoroacetic anhydride, acetic anhydride, chlorine, sulfur trioxide-pyridine complex and the like.

Method (d): A compound [I] in which the R³ or R⁴ is an alkyloxy group can be obtained by reacting a corresponding compound [I] in which R³ or R⁴ is a hydroxyl group with an alkyl halide in an appropriate solvent.

Method (e): Among the compound [I] of the present invention, a compound of the formula [I-b]:

wherein the symbols are the same as defined above can be obtained by treating a corresponding compound of the formula [I-c]:

wherein the symbols are the same as defined above with methanesulfonylchloride, heating to obtain a compound of the formula [X]:

wherein the symbols are the same as defined above and then hydrolyzing the product [X].

Method (f): A compound [I] in which the R³ or R⁴ is a hydroxyalkyl group can be obtained by reducing a corresponding compound [I] in which R³ or R⁴ is an alkyloxycarbonylalkyl group. The reduction can be carried out in the presence of a reducing agent such as lithium borohydride and the like.

Method (g): A compound [I] in which the R⁶ is an alkylamino-substituted heterocyclic group (e.g., an alkylaminopyridyl group) can be obtained by reacting a corresponding compound [I] in which R⁶ is a halogen-substituted heterocyclic group with an alkylamine in an appropriate solvent in the presence of a base (e.g., potassium carbonate, cesium carbonate).

Method (h): A compound [I] in which the R⁶ is an alkyloxy-substituted heterocyclic group (e.g., an alkyloxypyridyl group) can be obtained by reacting a corresponding compound [I] in which R⁶ is a halogen-substituted heterocyclic group with an alkanol in a solvent in the presence of a base (e.g., potassium carbonate, cesium carbonate).

Method (i): A compound [I] in which a substituent(s) in R⁶ is a group containing an amino group substituted by an acyl group (e.g., an alkyloxycarbonyl group, an alkylcarbonyl group, an arylalkyloxycarbonyl group, an alkylsulfonyl group, a amorpholinocarbonyl group, a mono- or dialkylcarbamoyl group a mono- or dialkylaminosulfonyl group or a halogenoalkylcarbonyl group) can be obtained by reacting a corresponding compound [I] in which the substituent in R⁶ is a group containing an amino group with an acylating agent containing the desired substituent in the same manner as described in Method A.

Method (j): A compound [I] in which the R³ or R⁴ is a nitrogen-containing heterocyclic group (e.g., 1-pyrrolidinyl group), namely a group of the formula:

wherein the Ring A is a 4- to 10-membered heterocyclic group can be obtained by converting a corresponding compound [I] in which R³ or R⁴ is a hydroxyl group to its reactive derivative (e.g., a corresponding compound having a methanesulfonyloxy group) and then reacting the reactive derivative with a cyclic amine compound of the formula:

wherein the symbol is the same as defined above in the presence of a base.

Method (k): A compound [I] in which the R³ or R⁴ is a mono- or di-alkyl-carbamoyl group can be obtained by reacting a corresponding compound [I] in which R³ or R⁴ is a carboxyl group with a mono- or dialkyl-amine compound in the same manner as described in Method A.

Method (l): A compound [I] in which the substituent(s) in R¹ and/or R² is an alkylsulfinyl (or alkylsulfonyl) group can be obtained by oxidizing the corresponding compound in which the substituent(s) in R¹ and/or R² is an alkylthio group. The oxidation can be carried out in a solvent (e.g., methylene chloride) in the presence of an oxidizing agent (e.g., m-chloroperbenzoic acid).

If necessary, the compounds [I] of the present invention obtained in the aforementioned Processes A to C or Methods (a) to (k) can be converted to a pharmaceutically acceptable salt thereof by a conventional manner.

A compound [II] as a synthetic intermediate for preparing the compound [I] of the present invention can be obtained by reacting a compound [IV] with a compound of the formula [XI]:

wherein G is an amino-protecting group and the other symbols are the same as defined above and then removing the amino-protecting group from the product.

The reaction of the compound [IV] with the compound [XI] can be carried out in the same manner as described in the aforementioned Method B. Examples of the amino-protecting group include an arylalkyloxycarbonyl group such as bezyloxycarbonyl group, an alkyloxycarbonyl group such as ethyloxycarbonyl group or tert-butoxycarbonyl group and the like.

A compound [V] mentioned above can be obtained by reacting a compound of the formula [XII]:

wherein the symbols are the same as defined above with a compound [III] and then removing the amino-protecting group from the product. The reaction of the compound [XII] with the compound [III] can be carried out in the same manner as described in the aforementioned Method A.

Among the above-mentioned compound [IV], a compound [IV] in which the reactive residue (X) is a hydroxyl group (compound [IV-a]) can be obtained by (1) reacting an aldehyde compound [VIII] with a Grignard reagent (or an organic lithium compound) [XIV], or (2) reducing a ketone compound [XV] as shown in the following reaction scheme wherein M is a halogenated magnesium or lithium and the other symbols are the same as defined above.

The reaction of the compound [XIII] with the Grignard reagent (or the organic lithium compound) [XIV] can be carried out in the presence or absence of a solvent. Examples of the solvent include any solvent which does not disturb the reaction, such as tetrahydrofuran, diethylether, 1,4-dimethoxyethane and the like.

The reduction of the compound [XV] can be carried out in the presence of a conventional reducing agent such as sodium borohydride, lithium borohydride, lithium aluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride and the like. The hydroxyl group (X) in a reaction product (compound [IV-a]) of such process can be converted, in a conventional manner, to other reactive residue (e.g., a halogen atom such as fluorine atom, chlorine atom, bromine atom or iodine atom, trifluoromethanesulfonyloxy group, p-toluenesulfonyloxy group, methanesulfonyloxy group, hydroxyl group and the like).

In conducting the above mentioned processes, when the starting materials or intermediate compounds have a functional group(s), if necessary, the protection of the functional groups and the following deprotection thereof may be carried out in accordance with a conventional manner.

Throughout the present description and claims, the “halogen atom” means fluorine, chlorine, bromine or iodine atom. The “alkyl group” means a straight or branched chain alkyl group having 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms. The “alkenyl group” means a straight or branched chain alkenyl group having 2 to 12 carbon atoms, preferably 2 to 6 carbon atoms. The “alkynyl group” means a straight or branched chain alkynyl group having 2 to 12 carbon atoms, preferably 2 to 6 carbon atoms. The “cycloalkyl group” means a cycloalkyl group having 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms. The “cycloalkenyl group” means a cycloalkenyl group having 3 to 10 carbon atoms, preferably 3 to 10 carbon atoms. The “alkyleneoxy group” means a straight or branched chain alkyleneoxy group having 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms. The “alkylenedioxy group” means a straight or branched chain alkylenedioxy group having 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms.

BEST MODE FOR CARRYING OUT THE INVENTION

The compounds of the present invention are illustrated in more detail by the following Examples but should not be construed to be limited thereto.

Example 1

To a solution of (3R)-1-[bis-(4-chlorophenyl)methyl]-3-aminopyrrolidine (2.05 g, compound obtained in Reference Example 11) and triethylamine (1.35 mL) in methylene chloride (30 mL) was added dropwise 4-(trifluoromethoxy)benzoyl chloride (1.21 mL) under ice-cooling and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added water and the mixture is extracted with chloroform (×2). The organic layer was filtered through a NH-silica gel (10 g of Chromatorex NH-silica gel; Fuji Silicia Chem.) and the filtrate was evaporated in vacuo. The crude product was triturated in ethyl acetate/hexane to obtain (3R)-1-[bis-(4-chlorophenyl)methyl]-3-[[4-(trifluoromethoxy)benzoyl]amino]pyrrolidine (2.70 g; yield: 83%) as crystals.

MS(APCI) m/z; 508/510 [M+H]⁺

Example 2

(1) A compound obtained in Reference Example 8 (2.01 g) was treated in the same manner as described in Reference Examples 11-(2) and 6-(2) to give (3,4-trans)-1-[bis-(4-chlorophenyl)methyl]-3-hydroxy-4-aminopyrrolidine dihydrochloride (2.13 g; yield: 51%). MS(APCI) m/z; 337/339 [M+H]⁺

(2) To a solution of the compound obtained in the above step (1) (1.50 g) and sodium hydrogencarbonate (1.55 g) in ethyl acetate (50 mL) and water (50 mL) was added dropwise 4-(trifluoromethoxy)benzoyl chloride (635 μL) under ice-cooling and the mixture was stirred at the same temperature for 1 hour. The organic layer was separated and filtered through a NH-silica gel bead (5 g of Chromatorex NH-silica gel) and the filtrate was evaporated in vacuo. The crude product was triturated in ethyl acetate/hexane to obtain (3,4-trans)-1-[bis-(4-chlorophenyl)methyl]-3-hydroxy-4-[[4-(trifluoromethoxy)benzoyl]amino]pyrrolidine (1.61 g; yield: 84%) as crystals.

MS(APCI) m/z; 525/527 [M+H]⁺

Example 3

To a solution of the compound obtained in Reference Example 11 (26.9 mg) and 6-methylnicotinic acid (20.5 mg) in chloroform (1 mL) was added successively a 0.5M 1-hydroxybenzotriazole/dimethylformamide (0.4 mL) and 0.5M 1-ethyl-3-[3-(dimethyl-amino)propyl]carbodiimide hydrochloride/chloroform (0.4 mL) and the mixture was stirred at room temperature overnight. To the reaction mixture was added an aqueous saturated sodium hydrogencarbonate solution (1 mL), water (2 mL) and chloroform (2 mL) and the mixture was stirred for 15 minutes. A chloroform layer in the mixture was separated and evaporated in vacuo. The crude product was purified by HPLC (XTerra Prep MS C18 column; solvent: 10 mM ammonium carbonate/methanol=80:20→5:95), dissolved in tert-butylalcohol (1.5 mL) and lyophilized to give (3R)-1-[bis-(4-chlorophenyl)methyl]-3-[(6-methylnicotinoyl)amino]pyrrolidine (40.7 mg; yield: 92%) as a powder. MS(ESI) m/z; 440/442 [M+H]⁺

Example 4

To a solution of 6-methylnicotinic acid (35 mg) in ethanol (1 mL) was added 2N sodium hydroxide solution (0.14 mL) and the mixture was stirred at 60° C. for 2 hours. After cooling to room temperature, to the reaction mixture was added 5N HCl (0.06 mL) and the mixture was evaporated in vacuo to give 6-methyloxynicotinic acid. The product was treated in the same manner as described in Example 3 to give (3R)-1-[bis-(4-chlorophenyl)methyl]-3-[(6-methoxynicotinoyl)amino]pyrrolidine (28.0 mg; yield: 61%) as a powder.

MS(ESI) m/z; 456/458 [M+H]⁺

Example 5

(1) The corresponding materials were treated in the same manner as described in Reference Examples 2 and 4-(3) to give bis-(4-ethoxyphenyl)methyl chloride.

(2) The compound obtained in the above step (1) (545 mg) was treated in the same manner as described in Reference Example 11 to give (3R)-1-[bis-(4-ethoxyphenyl)methyl]-3-(tert-butoxycarbonylamino)pyrrolidine (671 mg; yield: 76%).

MS(APCI) m/z; 441 [M+H]⁺

(3) To a solution of the compound obtained in the above step (2) (52 mg) in 1.5M 2,6-lutidine/methylene chloride (1 mL) was added 1.0M trimethylsilyl trifluoromethanesulfonate/methylene chloride (1 mL) and the mixture was stirred at room temperature for 25 hours. To the reaction mixture was added methanol (500 μL) and the mixture was diluted with chloroform and washed with an aqueous saturated sodium hydrogencarbonate solution. The organic layer was filtered through a NH-silica gel bead and evaporated in vacuo. The residue was dissolved in methylene chloride (2 mL) and thereto was added triethylamine (28 μL) and 4-(trifluoromethoxy)benzoyl chloride (26 μL). The mixture was stirred at room temperature for 15 hours. To the reaction mixture was added water and the mixture was extracted with chloroform. The extract was evaporated in vacuo and the residue was purified by HPLC (XTerra Prep MS C18 column; Waters Inc.; Solvent: water/methanol=1:1→5:95) to give (3R)-1-[bis-(4-ethoxyphenyl)methyl]-3-[[4-(trifluoromethoxy)benzoyl]amino]pyrrolidine (27.2 mg, yield: 38%) as an amorphous powder.

MS(APCI) m/z; 529 [M+H]⁺

Example 6

A mixture of [bis-(4-chlorophenyl)]chloromethane (compound obtained in Reference Example 11-(1), 342 mg), (3,4-trans)-3-(ethoxycarbonyl)-4-[[4-(trifluoro-methoxy)benzoyl]amino]pyrrolidine (375 mg, compound obtained in Reference Example 7) and diisopropylamine (0.44 mL) in dioxane was stirred at 85° C. overnight. The reaction mixture was evaporated to remove dioxane and the residue was purified by a column chromatography on silica gel (solvent; n-hexane/ethyl acetate=4:1) to give (3,4-trans)-1-[bis-(4-chlorophenyl)methyl]-3-(ethloxycarbonyl)-4-[[4-(trifluoromethoxy)-benzoyl]amino]pyrrolidine (249 mg, yield: 51%) as a powder.

MS(APCI) m/z; 581/583 [M+H]⁺

Example 7

(1) 4-Methoxybenzaldehyde (243 μL) was treated in the same manner as described in Reference Example 5-(1) to give (4-chlorophenyl)(4-methoxyphenyl)methanol (279 mg, yield: 56%).

MS(APCI) m/z; 231/233 [M+H−H₂O]⁺

(2) To a solution of the compound obtained in the above step (1) (220.6 mg) and triehylamine (250 μL) in methylene chloride (2 mL) was added methanesulfonyl chloride (82 μL) under ice-cooling and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added (3R)-3-[[4-(trifluoromethoxy)benzoyl]amino]-pyrrolidine (364 mg, compound obtained in Reference Example 6) and acetonitrile (3 mL) and the mixture was stirred at 80° C. for 16 hours. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The extract was evaporated in vacuo and the resultant crude product was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=4:1→2:1), dissolved in tert-butylalcohol (1.5 μL) and lyophilized to give (3R)-1-[(4-chlorophenyl)(4-methoxy-phenyl)methyl]-3-[[4-(trifluoromethoxy)benzoyl]amino]pyrrolidine (241.5 mg, yield: 54%) as a powder.

MS(ESI) m/z; 505/507 [M+H]⁺

Example 8

A mixture of the compound obtained in Example 1 (60 mg), tris(dibenzylideneacetone)dipalladium (8.6 mg), 1,1′-bis(diphenylphosphino)ferrocene (10.4 mg), zinc cyanide (16.6 mg) and zinc powder (3.7 mg) in dimethylacetamide (0.5 mL) was stirred at 200° C. for 10 minutes by using Microwave Synthetic System (Discover; CEM Ltd.). The reaction mixture was diluted with ethyl acetate and thereto was added water. The organic layer was separated and evaporated in vacuo. The residue was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=2:1→1:1), dissolved in tert-butylalcohol and lyophilized to give (3R)-1-[bis-(4-cyanophenyl)methyl]-3-[[4-(trifluoromethoxy)benzoyl]amino]pyrrolidine (32.1 mg, yield: 56%) as a powder.

MS(APCI) m/z; 491 [M+H]⁺

Example 9

A mixture of the compound obtained in Example 1 (50 mg), tris(dibenzylideneacetone)dipalladium (0.9 mg), 2-(dicyclohexylphosphino)-2′-(N,N-dimethylamino)biphenyl (1.5 mg), cyclopentylamine (24 μL) and 1.0M lithium bis(trimethylsilyl)amide/tetrahydrofuran (0.35 mL) was stirred at 110° C. for 10 minutes by using Microwave Synthetic System (Discover; CEM Ltd.). The reaction mixture was diluted with ethyl acetate and thereto was added water. The organic layer was separated and evaporated in vacuo. The residue was purified by HPLC (XTerra Prep MS C18 column; Waters Inc., solvent; water/methanol=1:1→5:95), dissolved in tert-buthanol and lyophilized to give (3R)-1-[bis-[4-(cyclopentylamino)phenyl]methyl]-3-[[4-(trifluoromethoxy)benzoyl]amino]pyrrolidine (18.7 mg, yield: 32%) as a powder.

MS(ESI) m/z; 639 [M+H+MeOH]⁺

Example 10

A mixture of the compound obtained in Example 1 (50 mg), tris(dibenzylideneacetone)dipalladium (0.9 mg), 2-(dicyclohexylphosphino)-2′-(N,N-dimethylamino)biphenyl (1.5 mg), n-butylmethylamine (29 μL) and 1.0M lithium bis(trimethylsilyl)amide/tetrahydrofuran (0.35 mL) was stirred at 110° C. for 10 minutes by using Microwave Synthetic System (Discover; CEM Ltd.). The reaction mixture was diluted with ethyl acetate and thereto was added water. The organic layer was separated and evaporated in vacuo. The residue was purified by HPLC (XTerra Prep MS C18 column; Waters Inc., solvent; water/methanol=1:1→5:95), dissolved in tert-buthanol and lyophilized to give (3R)-1-[[4-(n-butylmethylamino)phenyl](4-chlorophenyl)methyl]-3-[[4-(trifluoromethoxy)benzoyl]amino]pyrrolidine (12.6 mg, yield: 23%; compound a) and (3R)-1-[bis-[4-(n-butylmethylamino)phenyl]methyl]-3-[[4-(trifluoromethoxy)benzoyl]amino]pyrrolidine (18.0 mg, yield: 30%; compound b) as a powder, respectively.

Compound a: MS(ESI) m/z; 560/562 [M+H]⁺

Compound b: MS(ESI) m/z; 643 [M+H+MeOH]⁺

Example 11

To a solution of dimethylsulfoxide (54 μL) in methylene chloride (2 mL) was added trifluoroacetic anhydride (86 μL) under nitrogen gas atmosphere and under cooling in dry ice/acetone bath and the mixture was stirred for 10 minutes. Thereto was added a suspension of the compound obtained in Example 2 (99 mg) in methylene chloride (4 mL) and the mixture was stirred at the same temperature for 1 hour. Thereto was added diisopropylethylamine (215 μL) and the mixture was stirred for 40 minutes. To the reaction mixture was added methanol (0.2 mL) and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added water and the mixture was extracted with chloroform. The extract was evaporated in vacuo and the residue was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=9:1→2:1) to give 1-[bis-(4-chlorophenyl)methyl]-3-oxo-4-[[4-(trifluoromethoxy)benzoyl]-amino]pyrrolidine (41.5 mg; yield: 43%) as an amorphous powder.

MS(ESI) m/z; 523/525 [M+H]⁺

Example 12

To a solution of (3S,4R)-1-[bis-(4-chlorophenyl)methyl]-3-hydroxy-4-[[4-(trifluoromethoxy)benzoyl]amino]pyrrolidine (75.6 mg, an optical isomer of the compound obtained in Example 2) in acetonitrile (8 mL)/dimethylformamide (2 mL) was added successively methyl iodide (233 μL) and silver oxide (216.8 mg) and the mixture was stirred at room temperature for 23 hours. The reaction mixture was filtered through Cerite, washed with acetonitrile and evaporated in vacuo. The crude product was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=4:1→2:1) to give (3S,4R)-1-[bis-(4-chlorophenyl)methyl]-3-methoxy-4-[[4-(trifluoro-methoxy)benzoyl]amino]pyrrolidine (39.5 mg; yield: 51%) as an amorphous powder.

MS(ESI) m/z; 539/541 [M+H]⁺

Example 13

(1) To a solution of the compound obtained in Example 2 (400 mg) and triethylamine (215 μL) in chloroform (8 mL) was added dropwise methanesulfonyl chloride (83 μL) under nitrogen gas atmosphere and ice-cooling and the mixture was stirred at 60° C. for 2 hours. After cooling to room temperature, to the reaction mixture was added water and the organic layer was separated and evaporated in vacuo. The crude product was purified by a flash column chromatography on NH-silica gel (Chromatorex NH-silica gel; Fuji Silicia Chem., solvent: hexane/ethyl acetate=2:1→0:1) to give 5-[bis-(4-chlorophenyl)methyl]-2-[4-(trifluoromethoxy)phenyl]-3a,6a-dihydro-3-pyrrolino[3,4-d]oxazole (361 mg, yield: 94%) as an amorphous powder.

MS(APCI) m/z; 507/509 [M+H]⁺

(2) To a solution of the compound obtained in the above step (1) (360 mg) in methanol (2.5 mL) was added 6N HCl (1.5 mL) and the mixture was stirred at 65° C. for 30 minutes. After cooling to room temperature, the reaction mixture was diluted with tetrahydrofuran, treated with cation-exchange resin (ISOLUTE SCX; IST Ltd., solvent: methanol/tetrahydrofuran=1:1→1N ammonia/methanol) and evaporated in vacuo to give (3,4-cis)-1-[bis-(4-chlorophenyl)methyl]-3-hydroxy-4-[[4-(trifluoromethoxy)-benzoyl]amino]pyrrolidine (301 mg, yield: 81%) as an amorphous powder.

MS(APCI) m/z; 525/527 [M+H]⁺

Example 14

To a solution of the compound obtained in Example 482 (100 mg) in tetrahydrofuran/ethanol was added lithium borohydride (13 mg) and the mixture was stirred at room temperature for 15 hours. The reaction mixture was evaporated in vacuo and to the residue was added a potassium hydrogensulfate solution. The mixture was extracted with ethyl acetate and the organic layer was evaporated in vacuo. The crude product was purified by a column chromatography on silica gel (solvent; ethyl acetate/hexane=1:1) to give (2S,4R)-1-[bis-(4-chlorophenyl)methyl]-2-hydroxy-methyl-4-[(4-chlorobenzoyl)amino]pyrrolidine (72 mg, yield: 73%) as a powder.

MS(APCI) m/z; 489/491 [M+H]⁺

Example 15

To a solution of the compound obtained in Example 27 (32 mg) in N-methylpyrrolidone was added potassium carbonate (26 mg) and 1N dimethylamine/methanol (0.5 mL) and the mixture was stirred at 100° C. for 15 hours. To the reaction mixture was added water and the mixture was extracted with chloroform. The organic layer was evaporated in vacuo and the crude product was purified by a column chromatography on silica gel (solvent; ethyl acetate/hexane=1:1) to give (3R)-1-[bis-(4-chlorophenyl)methyl]-3-[[6-(dimethylamino)nicotinoyl]amino]pyrrolidine (8 mg, yield: 37%) as a powder.

MS(APCI) m/z; 469/471 [M+H]⁺

Example 16

To a solution of (3R)-1-[bis-(4-chlorophenyl)methyl]-3-[(5-bromonicotinoyl)-amino]pyrrolidine (50 mg) in toluene was added copper iodide (7 mg), cesium carbonate (15 mg), sodium iodide (15 mg), phenanthroline (14 mg) and ethanol (0.1 mL) and the mixture was stirred at 100° C. for 15 hours. The reaction mixture was evaporated in vacuo and to the residue was added an aqueous saturated sodium hydrogencarbonate solution was added. The mixture was extracted with ethyl acetate and the organic layer was evaporated in vacuo. The residue was purified by a column chromatography on silica gel (solvent; ethyl acetate/hexane=1:1) to give (3R)-1-[bis-(4-chlorophenyl)methyl]-3-[(5-ethoxynicotinoyl)amino]pyrrolidine (12 mg, yield: 26%) as a powder.

MS(APCI) m/z; 470/472 [M+H]⁺

Example 17

To the compound obtained in Example 46 (20 mg) was added 4N HCl/dioxane and the mixture was stirred at room temperature for 15 hours. The reaction mixture was evaporated in vacuo to give (3R)-1-[bis-(4-chlorophenyl)methyl]-3-[((2S)-2-amino-3-phenylpropionyl)amino]pyrrolidine. To the compound was added triethylamine (0.05 mL) and chloroform and then added dropwise 4-morpholincarbonyl chloride (0.03 mL) under ice-cooling. The mixture was stirred at room temperature for 15 hours. To the reaction mixture was added an aqueous saturated sodium hydrogencarbonate solution and the mixture was extracted. The organic layer was separated and evaporated and, the residue was purified by a column chromatography on silica gel (solvent; ethyl acetate/hexane=1:1) to give (3R)-1-[bis-(4-chlorophenyl)methyl]-3-[[(2S)-2-(morpholinocarbonylamino)-3-phenylpropionyl]amino]pyrrolidine (12 mg, yield: 58%) as a powder.

MS(ESI) m/z; 581 [M+H]⁺

Example 18

(1) To a solution of the compound obtained in Example 13 (60 mg) and triethylamine (24 μL) in methylene chloride (1 mL) was added dropwise methanesulfonyl chloride (11 μL) under ice-cooling and the mixture was stirred for 30 minutes. The reaction mixture was diluted with ethyl acetate. After adding water, the organic layer was separated and evaporated in vacuo. The crude product was purified by a flash column chromatography on NH-silica gel (Chromatorex NH-silica gel, solvent; hexane/ethyl acetate=4:1→0:1), dissolved in tert-butylalcohol (1.5 μL) and lyophilized to give (3,4-cis)-1-[bis-(4-chlorophenyl)methyl]-3-methanesulfonyloxy-4-[[4-(trifluoromethoxy)-benzoyl]amino]pyrrolidine (38.2 mg, yield: 56%) as a powder.

MS(APCI) m/z; 603/605 [M+H]⁺

(2) To a solution of the compound obtained in the above step (1) (31.3 mg) in dimethylformamide (0.3 mL) was added pyrrolidine (45 μL) and the mixture was stirred at 150° C. for 10 minutes by using Microwave Synthetic System (Discover). The reaction mixture was diluted with ethyl acetate. After adding water, the organic layer was separated and evaporated in vacuo. The crude product was purified by HPLC (XTerra Prep MS C18 column, solvent; water/methanol=1:1→5:95), dissolved in tert-butylalcohol and lyophilized to give (3,4-trans)-1-[bis-(4-chlorophenyl)methyl]-3-(1-pyrrolidinyl)-4-[[4-(trifluoromethoxy)benzoyl]amino]pyrrolidine (13.2 mg, yield: 44%) as a powder.

MS(APCI) m/z; 578/580 [M+H]⁺

Example 19

(1) To a solution of the compound obtained in Example 6 (248.8 mg) in methanol (3 mL) and tetrahydrofuran (3 mL) was added 1N sodium hydroxide solution (0.86 mL) under ice-cooling and the mixture was stirred at room temperature for 4 hours. The reaction mixture was evaporated in vacuo and the residue was acidified with an aqueous saturated citric acid solution (about pH 3). The mixture was extracted with ethyl acetate and the organic layer was washed with water and a saturated brine, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated in diisopropylether and the resultant solid materials were collected by filtration to give (3,4-trans)-1-[bis-(4-chloro-phenyl)methyl]-3-carboxy-4-[[4-(trifluoromethoxy)benzoyl]amino]pyrrolidine (181.1 mg, yield: 76%) as a solid.

MS(APCI) m/z; 553/555 [M+H]⁺

(2) To a solution of the compound obtained in the above step (1) (30.0 mg) in dimethylformamide (1.0 mL) was added 1-hydroxybenzotriazole (17 mg) and 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (21 mg) and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added N,N′-dimethylethylenediamine (0.011 mL) and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water/ethyl acetate. The organic layer was washed successively with an aqueous saturated sodium hydrogencarbonate solution, water and a saturated brine, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated and the resultant solid materials were collected by filtration to give (3,4-trans)-1-[bis-(4-chlorophenyl)methyl]-3-[2-(dimethylamino)ethylcarbamoyl]-4-[[4-(trifluoromethoxy)benzoyl]amino]pyrrolidine (25.1 mg, yield: 75%) as a powder.

MS(APCI) m/z; 623/625 [M+H]⁺

Example 20

To a solution of N,N′-carbonyldiimidazole (16 mg) in tetrahydrofuran was added dropwise a solution of the compound obtained in Reference Example 11 (32 mg) in tetrahydrofuran under ice-cooling and the mixture was stirred for 30 minutes. To the mixture was added dropwise 1,2,3,4-tetrahydroisoquinoline (13 mg) and the mixture was stirred at room temperature for 15 hours. The reaction mixture was evaporated in vacuo and thereto was added an aqueous saturated sodium hydrogencarbonate solution. The mixture was extracted with chloroform and the extract was evaporated in vacuo. The crude product was purified by a column chromatography on silica gel (solvent; ethyl acetate/hexane) to give (3R)-1-[bis-(4-chlorophenyl)methyl]-3-[(2-1,2,3,4-tetrahydro isoquinolyl)carbonylamino]pyrrolidine (30 mg, yield: 62%) as a powder.

MS(APCI) m/z; 480/482 [M+H]⁺

Example 21

A mixture of the compound obtained in Reference Example 11 (32.1 mg), 4-cyanobenzoic acid (29.4 mg), 1-hydroxyazabenzotriazole (20.4 mg), N-cyclohexyl-carbodiimide-N′-propyloxymethylpolystyrene (PS-carbodiimide, 275 mg) and dimethylformamide (2 mL) was stirred at room temperature overnight by using a parallel synthetizer (MiniBlock; Mettler Toledo). The reaction mixture was filtered and the resin was washed with dimethylformamide (1 mL×2). To the filtrate was added macroporous triethylammoniummethylpolystyrenecarbonate (265.2 mg) and tris(2-aminoethyl)aminomethyl polystyrene (82.9 mg) and the mixture was stirred at room temperature overnight. The reaction mixture was treated with a cation-exchange resin (ISOLUTE SCX; IST Ltd.) and washed with dimethylformamide. The objective product was eluted with 10% ammonia-methanol and purged by nitrogen gas to remove solvent. The residue was purified by a column chromatography on silica gel (ISOLUTE SI; IST Ltd., solvent; chloroform/hexane=20:1→chloroform→chloroform/ethyl acetate=10:1), evaporated in vacuo and lyophilized to give (3R)-1-[bis-(4-chlorophenyl)methyl]-3-[(4-cyanobenzoyl)amino]pyrrolidine (30.9 mg, yield: 69%) as a powder.

MS(APCI) m/z; 450/452 [M+H]⁺

Example 22

(1) 4-Bromobenzaldehyde (4.0 g) was treated in the same manner as described in reference Example 5 to give chloro(4-chlorophenyl)(4-bromophenyl)methane (5.08 g, yield: 75%). MS(APCI) m/z; 279/281 [M+H−HCl]⁺

(2) The compound obtained in the above step (1) (1.73 g) was treated in the same manner as described in Example 6 to give 1-[(4-bromophenyl)(4-chlorophenyl)methyl]-3-[[4-(trifluoromethoxy)benzoyl]amino]pyrrolidine (1.65 g, yield: 82%).

MS(APCI) m/z; 553/555 [M+H]⁺

(3) A mixture of the compound obtained in the above step (2) (60 mg), tris(dibenzylideneacetone)dipalladium (4.0 mg), 1,1′-bis(diphenylphosphino)ferrocene (4.8 mg), zinc cyanide (7.6 mg), water (50 μL) and dimethylformamide (0.5 mL) was stirred at 200° C. for 10 minutes by using a microwave synthetic system (Discover; CEM). The reaction mixture was diluted with ethyl acetate. After adding water, the organic layer was separated and evaporated in vacuo. The crude product was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=4:1→1:1), dissolved in tert-butylalcohol and lyophilized to give 1-[(4-chlorophenyl)(4-cyanophenyl)-methyl]-3-[[4-(trifluoromethoxy)benzoyl]amino]pyrrolidine (13.4 mg, yield: 25%) as a powder.

MS(APCI) m/z; 500/502 [M+H]⁺

Examples 23 to 431

The corresponding materials were treated in the same manner as described in one of the aforementioned Examples 1 to 5 to give the compounds as shown in the following Table 1 (Nos. 1 to 68).

TABLE 1 (No. 1)

Ex. Nos. R R′ Physicochemical properties etc. 23

powder MS(APCI)539/541[M + H]+ 24

powder MS(APCI)489/491[M + H]+ 25

powder MS(APCI)553/555[M + H]+ 26

powder MS(APCI)503/505[M + H]+ Me: methyl group, Et: ethyl group

TABLE 1 (No. 2)

Ex.Nos. R Physicochemical properties etc. 27

powder MS(APCI)460/462[M + H]+ 28

powder MS(APCI)494/496[M + H]+ 29

powder MS(APCI)504/506[M + H]+ 30

powder MS(APCI)529/531[M + H]+ 31

oil MS(APCI)554/556[M + H]+ 32

powder MS(APCI)554/556[M + H]+ Boc: tert-butyloxycarbonyl group

TABLE 1 (No. 3)

Ex. Nos. R Physicochemical properties etc. 33

powder MS(APCI)485/487[M + H]+ 34

solid MS(APCI)421/423[M + H]+ 35

solid MS(APCI)407/409[M + H]+ 36

solid MS(APCI)449/451[M + H]+ 37

solid MS(APCI)435/437[M + H]+ 38

solid MS(APCI)433/435[M + H]+ 39

solid MS(APCI)447/449[M + H]+ 40

solid MS(APCI)461/463[M + H]+ 41

solid MS(APCI)475/477[M + H]+ Me: methyl group, Et: ethyl group, n-Bu: n-butyl group, t-Bu: tert-butyl group

TABLE 1 (No. 4)

Ex. Nos. R Physicochemical properties etc. 42

solid MS(APCI)496/498[M + H]+ 43

solid MS(APCI)469/471[M + H]+ 44

powder MS(APCI)469/471[M + H]+ 45

powder MS(APCI)568/570[M + H]+ 46

powder MS(APCI)568/570[M + H]+ 47

powder MS(APCI)598/600[M + H]+ Me: methyl group, Boc: tert-butyloxycarbonyl group

TABLE 1 (No. 5)

Ex. Nos. R Physicochemical properties etc. 48

powder MS(APCI)483/485[M + H]+ 49

powder MS(APCI)5O4/5O6[M + H]+ 50

powder MS(APCI)440/442[M + H]+ 51

powder MS(APCI)443/445[M + H]+ 52

powder MS(APCI)507/509[M + H]+ 53

powder MS(APCI)542/544[M + H]+ Me: methyl group

TABLE 1 (no. 6)

Ex. Nos. R Physicochemical properties etc. 54

powder MS(APCI)529/531[M + H]+ 55

powder MS(APCI)523/525[M + H]+ 56

powder MS(APCI)543/545[M + H]+ 57

powder MS(APCI)578/580[M + H]+ 58

powder MS(APCI)460/462[M + H]+ 59

powder MS(APCI)485/487[M + H]+ Me: methyl group

TABLE 1 (No. 7)

Ex. Nos. R Physicochemical properties etc. 60

powder MS(APCI)475/477[M + H]+ 61

powder MS(APCI)475/477[M + H]+ 62

powder MS(APCI)469/471[M + H]+ 63

powder MS(APCI)465/467[M + H]+ 64

powder MS(APCI)405/407[M + H]+ 65

powder MS(APCI)419/421[M + H]+ 66

powder MS(APCI)521/523[M + H]+ Me: methyl group

TABLE 1 (No. 8)

Ex. Nos. R Physicochemical properties etc. 67

powder MS(APCI)503/505[M + H]+ 68

powder MS(APCI)467/469[M + H]+ 69

powder MS(APCI)471/473[M + H]+ 70

powder MS(APCI)537/539[M + H]+ 71

powder MS(APCI)521/523[M + H]+ 72

powder MS(APCI)487/489[M + H]+ 73

powder MS(APCI)521/523[M + H]+ Me: methyl group

TABLE 1 (No. 9)

Ex. Nos. R Physicochemical properties etc. 74

powder MS(APCI)455/457[M + H]+ 75

powder MS(APCI)493/495[M + H]+ 76

powder MS(APCI)460/462[M + H]+ Me: methyl group

TABLE 1 (No. 10)

Ex. Nos. R Physicochemical properties etc. 77

powder MS(APCI)445[M + H]+ 78

powder MS(APCI)419/421[M + H]+ 79

powder MS(APCI)411[M + H]+ 80

powder MS(APCI)421[M + H]+ Me: methyl group

TABLE 1 (No. 11)

Ex. Physicochemical Nos. R R′ properties etc. 81 H

powder MS(SSI)426 82 Me

powder MS(SSI)400 Me: methyl group

TABLE 1 (No. 12)

Ex. Physicochemical Nos. R properties etc. 83

powder MS(SSI)501 84

powder MS(SSI)475 85

powder MS(SSI)426 86

powder MS(SSI)468 87

powder MS(SSI)425 88

powder MS(SSI)467 89

powder MS(SSI)453 Me: methyl group

TABLE 1 (No. 13)

Ex. Physicochemical Nos. R properties etc. 90

powder MS(SSI)431 91

powder MS(SSI)475 92

powder MS(SSI)439 93

powder MS(SSI)455 94

powder MS(SSI)560 95

powder MS(SSI)546 96

powder MS(SSI)568 Boc: tert-butyloxycarbonyl group

TABLE 1 (No. 14)

Ex. Physicochemical Nos. R properties etc. 97

powder MS(SSI)626 98

powder MS(SSI)640 99

powder MS(SSI)492 100

powder MS(SSI)463 101

powder MS(SSI)536 102

powder MS(SSI)622 Boc: tert-butyloxycarbonyl group

TABLE 1 (No. 15)

Ex. Physicochemical Nos. R properties etc. 103

powder MS(APCI) 568/570 [M + H]+ 104

powder MS(APCI) 568/570[M + H]+ 105

powder MS(SSI)532 106

powder MS(SSI)574 107

powder MS(SSI)467 108

powder MS(SSI)454 109

powder MS(SSI)494 Me: methyl group, Boc: tert-butyloxycarbonyl group

TABLE 1 (No. 16)

Ex. Physicochemical Nos. R properties etc. 110

powder MS(SSI)479 111

powder MS(SSI)455 112

powder MS(SSI)454 113

powder MS(SSI)483 114

powder MS(SSI)487 115

powder MS(SSI)522 116

powder MS(SSI)487 Me: methyl group

TABLE 1 (No. 17)

Ex. Physicochemical Nos. R properties etc. 117

powder MS(SSI)467 118

powder MS(SSI)497 119

powder MS(SSI)513 120

powder MS(SSI)471 121

powder MS(SSI)467 122

powder MS(SSI)522 123

powder MS(SSI)521 Me: methyl group

TABLE 1 (No. 18)

Ex. Physicochemical Nos. R properties etc. 124

powder MS(SSI)589 125

powder MS(SSI)589 126

powder MS(SSI)489 127

powder MS(SSI)537 128

powder MS(SSI)487 129

powder MS(SSI)522 130

powder MS(SSI)471

TABLE 1 (No. 19)

Ex. Physicochemical Nos. R properties etc. 131

powder MS(SSI)471 132

powder MS(SSI)503 133

powder MS(SSI)517 134

powder MS(SSI)578 135

powder MS(SSI)485 136

powder MS(SSI)560 Me: methyl group, Boc: tert-butyloxycarbonyl group

TABLE 1 (No. 20)

Ex. Physicochemical Nos. R properties etc. 137

powder MS(SSI)574 138

powder MS(SSI)509 139

powder MS(SSI)639 140

powder MS(SSI)564 141

powder MS(SSI)588 142

powder MS(SSI)494 143

powder MS(SSI)498 Me: methyl group, Et: ethyl group

TABLE 1 (No. 21)

Ex. Physicochemical Nos. R properties etc. 144

powder MS(SSI)551 145

powder MS(SSI)521 146

powder MS(SSI)641 147

powder MS(SSI)554 148

powder MS(SSI)544 149

powder MS(SSI)592 Boc: tert-butyloxycarbonyl group

TABLE 1 (No. 22)

Ex. Physicochemical Nos. R properties etc. 150

powder MS(SSI)600 151

powder MS(SSI)419 152

powder MS(SSI)551 153 n-Bu powder MS(SSI)405 154

powder MS(SSI)552 155

powder MS(SSI)445 156

powder MS(SSI)431 Me: methyl group, n-Bu: n-butyl group

TABLE 1 (No. 23)

Ex. Physicochemical Nos. R properties etc. 157

powder MS(SSI)472 158

powder MS(SSI)529 159

powder MS(SSI)531 160

powder MS(SSI)507 161

powder MS(SSI)457 162

powder MS(SSI)529 Me: methyl group

TABLE 1 (No. 24)

Ex. Physicochemical Nos. R properties etc. 163

powder MS(SSI)543 164

powder MS(SSI)439 165

powder MS(SSI)439 166

powder MS(SSI)565 167

powder MS(SSI)565 168

powder MS(SSI)457 169

powder MS(SSI)469 Me: methyl group

TABLE 1 (No. 25)

Ex. Physicochemical Nos. R properties etc. 170

powder MS(SSI)443 171

powder MS(SSI)443 172

powder MS(SSI)445 173

powder MS(SSI)515 174

powder MS(SSI)407 175

powder MS(SSI)553 176

powder MS(SSI)483 Me: methyl group

TABLE 1 (No. 26)

Ex. Physicochemical Nos. R properties etc. 177

powder MS(SSI)483 178

powder MS(SSI)481 179

powder MS(SSI)465 180

powder MS(SSI)469 181

powder MS(SSI)440 182

powder MS(SSI)508 183

powder MS(SSI)452 Me: methyl group

TABLE 1 (No. 27)

Ex. Physicochemical Nos. R properties etc. 184

powder MS(SSI)403 185

powder MS(SSI)513 186

powder MS(SSI)487 187

powder MS(SSI)475 188

powder MS(SSI)585 189

powder MS(SSI)475 190

powder MS(SSI)518 Me: methyl group

TABLE 1 (No. 28)

Ex. Physicochemical Nos. R properties etc. 191

powder MS(SSI)473 192

powder MS(SSI)504 193

powder MS(SSI)474 194

powder MS(SSI)469 195

powder MS(SSI)504 196

powder MS(SSI)494 Me: methyl group

TABLE 1 (No. 29)

Ex. Physicochemical Nos. R properties etc. 197

powder MS(SSI)473 198

powder MS(SSI)499 199

powder MS(SSI)513 200

powder MS(SSI)485 201

powder MS(SSI)447 202

powder MS(SSI)495 Me: methyl group, Et: ethyl group

TABLE 1 (No. 30)

Ex. Physicochemical Nos. R properties etc. 203

powder MS(SSI)494 204

powder MS(SSI)460 205

powder MS(SSI)478 206

powder MS(SSI)517 207

powder MS(SSI)569 208

powder MS(SSI)509 209

powder MS(SSI)578 Me: methyl group

TABLE 1 (No. 31)

Ex. Physicochemical Nos. R properties etc. 210

powder MS(SSI)495 211

powder MS(SSI)555 212

powder MS(SSI)548 213

powder MS(SSI)543 214

powder MS(SSI)494 215

powder MS(SSI)494 Me: methyl group

TABLE 1 (No. 32)

Ex. Physicochemical Nos. R properties etc. 216

powder MS(SSI)508 217

powder MS(SSI)587 218

powder MS(SSI)542 219

powder MS(SSI)523 220

powder MS(SSI)492 Me: methyl group

TABLE 1 (No. 33)

Ex. Physicochemical Nos. R properties etc. 221

powder MS(SSI)529 222

powder MS(SSI)469 223

powder MS(SSI)469 224

powder MS(SSI)569 225

powder MS(SSI)569 226

powder MS(SSI)487 Me: methyl group

TABLE 1 (No. 34)

Ex. Physicochemical Nos. R properties etc. 227

powder MS(SSI)506 228

powder MS(SSI)567 229

powder MS(SSI)539 230

powder MS(SSI)480 231

powder MS(SSI)570 232

powder MS(SSI)508 Me: methyl group

TABLE 1 (No. 35)

Ex. Physicochemical Nos. R properties etc. 233

powder MS(SSI)544 234

powder MS(SSI)526 235

powder MS(SSI)501 236

powder MS(SSI)539 237

powder MS(SSI)496 Et: ethyl group

TABLE 1 (No. 36)

Ex. Physicochemical Nos. R properties etc. 238

powder MS(SSI)478 239

powder MS(SSI)547 240

powder MS(SSI)535 241

powder MS(SSI)479 242

powder MS(SSI)510 Me: methyl group

TABLE 1 (No. 37)

Ex. Physicochemical Nos. R properties etc. 243

powder MS(SSI)542 244

powder MS(SSI)521 245

powder MS(SSI)480 246

powder MS(SSI)517 247

powder MS(SSI)510 248

powder MS(SSI)597 Me: methyl group

TABLE 1 (No. 38)

Ex. Physicochemical Nos. R properties etc. 249

powder MS(SSI)481 250

powder MS(SSI)508 251

powder MS(SSI)575 252

powder MS(SSI)497 253

powder MS(SSI)473 254

powder MS(SSI)519 Me: methyl group

TABLE 1 (No. 39)

Ex. Physicochemical Nos. R properties etc. 255

powder MS(SSI)493 256

powder MS(SSI)561 257

powder MS(SSI)538 258

powder MS(SSI)493 259

powder MS(SSI)443 260

powder MS(SSI)532 261

powder MS(SSI)545

TABLE 1 (No. 40)

Ex. Physicochemical Nos. R properties etc. 262

powder MS(SSI)440 263

powder MS(SSI)419 264

powder MS(SSI)403 265

powder MS(SSI)433 266

powder MS(SSI)445 267

powder MS(SSI)517 268

powder MS(SSI)517 269

powder MS(SSI)537 Me: methyl group

TABLE 1 (No. 41)

Ex. Physicochemical Nos. R properties etc. 270

powder MS(SSI)493 271

powder MS(SSI)513 272

powder MS(SSI)511 273

powder MS(SSI)511 274

powder MS(SSI)501 275

powder MS(SSI)553 Me: methyl group

TABLE 1 (No. 42)

Ex. Physicochemical Nos. R properties etc. 276

powder MS(SSI)519 277

powder MS(SSI)473 278

powder MS(SSI)497 279

powder MS(SSI)467 280

powder MS(SSI)527 281

powder MS(SSI)529 Me: methyl group, Et: ethyl group, n-Pr: n-propyl group

TABLE 1 (No. 43)

Ex. Physicochemical Nos. R properties etc. 282

powder MS(SSI)547 283

powder MS(SSI)517 284

powder MS(SSI)507 285

powder MS(SSI)527 286

powder MS(SSI)533 287

powder MS(SSI)588 Me: methyl group, n-Pr: n-propyl group

TABLE 1 (No. 44)

Ex. Physicochemical Nos. R properties etc. 288

powder MS(SSI)527 289

powder MS(SSI)529 290

powder MS(SSI)490 291

powder MS(SSI)490 292

powder MS(SSI)478 293

powder MS(SSI)539 294

powder MS(SSI)507 Me: methyl group

TABLE 1 (No. 45)

Ex. Physicochemical Nos. R properties etc. 295

powder MS(SSI)428 296

powder MS(SSI)464 297

powder MS(SSI)415 298

powder MS(SSI)521 299

powder MS(SSI)570 300

powder MS(SSI)540 Me: methyl group

TABLE 1 (No. 46)

Ex. Physicochemical Nos. R properties etc. 301

powder MS(SSI)564 302

powder MS(SSI)558 303

powder MS(SSI)476 304

powder MS(SSI)505 305

powder MS(SSI)460 306

powder MS(SSI)460 307

powder MS(SSI)504 Et: ethyl group

TABLE 1 (No. 47)

Ex. Physicochemical Nos. R properties etc. 308

powder MS(SSI)457 309

powder MS(SSI)494 310

powder MS(SSI)459 311

powder MS(SSI)483 312

powder MS(SSI)534 313

powder MS(SSI)455 314

powder MS(SSI)455 Me: methyl group i-Pr: isopropyl group

TABLE 1 (No. 48)

Ex. Physicochemical Nos. R properties etc. 315

powder MS(SSI)441 316

powder MS(SSI)445 317

powder MS(SSI)533 318

powder MS(SSI)518 319

powder MS(SSI)449 320

powder MS(SSI)482 321

powder MS(SSI)471 322

powder MS(SSI)455 Me: methyl group

TABLE 1 (No. 49)

Ex. Physicochemical Nos. R properties etc. 323

powder MS(SSI)507 324

powder MS(SSI)433 325

powder MS(SSI)451 326

powder MS(SSI)483 327

powder MS(SSI)554 328

powder MS(SSI)540 329

powder MS(SSI)452 330

powder MS(SSI)452 Boc: tert-butoxycarbonyl group

TABLE 1 (No. 50)

Ex. Physicochemical Nos. R properties etc. 331

powder MS(SSI)509 332

powder MS(SSI)541 Me: methyl group

TABLE 1 (No. 51)

Ex. Nos. R Physicochemical properties etc. 333

Powder MS(SSI)495 334

Powder MS(SSI)571 335

Powder MS(SSI)610 336

Powder MS(SSI)511 337

Powder MS(SSI)483 338

Powder MS(SSI)450 339

Powder MS(SSI)511 Me: methyl group

TABLE 1 (No. 52)

Physicochemical Ex. Nos. R properties etc. 340

Powder MS(SSI)477 341

Powder MS(SSI)463 342

Powder MS(SSI)449 343

Powder MS(SSI)435 344

Powder MS(SSI)481 345

Powder MS(SSI)467 346

Powder MS(SSI)495 Me: methyl group, i-Pr: isopropyl group, t-Bu: tert-butyl group

TABLE 1 (No. 53)

Physicochemical properties Ex. Nos. R etc. 347

Powder MS(SSI)506 348

Powder MS(SSI)479 349

Powder MS(SSI)492 350

Powder MS(SSI)483 351

Powder MS(SSI)465 352

Powder MS(SSI)505 Me: methyl group

TABLE 1 (No. 54)

Physicochemical properties Ex. Nos. R etc. 353

Powder MS(SSI)469 354

Powder MS(SSI)453 355

Powder MS(SSI)389 356

Powder MS(SSI)473 357

Powder MS(SSI)459 358

Powder MS(SSI)445 Me: methyl group

TABLE 1 (No. 55)

Ex. Nos. R Physicochemical properties etc. 359

Powder MS(APCI)568/570[M + H]+ 360

Powder MS(APCI)568/570[M + H]+ 361

Powder MS(APCI)469/471[M + H]+ 362

Powder MS(APCI)469/471[M + H]+ 363

resin MS(APCI)426/428[M + H]+ 354

resin MS(APCI)453/455[M + H]+ Boc: tert-butyloxycarbonyl group

TABLE 1 (No. 56)

Ex. Nos. R Physicochemical properties etc. 365

Powder MS(ESI)570 366

Powder MS(APCI)538/540[M + H]+ 367

Powder MS(APCI)497/499[M + H]+ 368

Powder MS(APCI)493/495[M + H]+ 369

Powder MS(APCI)493/495[M + H]+ 370

Powder MS(APCI)588/590[M + H]+ 371

Powder MS(APCI)589/591[M + H]+ n-Pr: n-propyl group

TABLE 1 (No. 57)

Ex. Nos. R Physicochemical properties etc. 372

Powder MS(APCI)589/591[M + H]+ 373

Powder MS(APCI)489/491[M + H]+ 374

Powder MS(APCI)487/489[M + H]+ 375

Powder MS(APCI)478/480[M + H]+ 376

Powder MS(APCI)473/475[M + H]+ 377

Powder MS(APCI)519/521[M + H]+ 378

Powder MS(APCI)490/492[M + H]+ Me: methyl group

TABLE 1 (No. 58)

Ex. Nos. R Physicochemical properties etc. 379

Powder MS(APCI)459/461[M + H]+ 380

Powder MS(APCI)483/485[M + H]+ 381

Powder MS(APCI)451/453[M + H]+ 382

solid MS(APCI)419/421[M + H]+ 383

solid MS(APCI)479/481[M + H]+ Me: methyl group, i-Pr: isopropyl group, n-Bu: n-butyl group

TABLE 1 (No. 59)

Ex. Nos. R Physicochemical properties etc. 384

Powder MS(APCI)507/509[M + H]+ 385

Powder MS(APCI)479/481[M + H]+ 386

Powder MS(APCI)419/421[M + H]+ Me: methyl group, Et: ethyl group, i-Pr: isopropyl group

TABLE 1 (No. 60)

Ex. Nos. R Physicochemical properties etc. 387

Powder MS(APCI)557[M + H]+ 388

Powder MS(APCI)469[M + H]+ Me: methyl group, i-Pr: isopropyl group

TABLE 1 (No. 61)

Ex. Nos. R Physicochemical properties etc. 389

powder MS(APCI)581/583[M + H]+ 390

powder MS(APCI)525/527[M + H]+ Et: ethyl group

TABLE 1 (No. 62)

Ex. Nos. R Physicochemical properties etc. 391 —CF₃ powder MS(APCI)433/435[M + H]+ 392

powder MS(APCI)475/477[M + H]+

TABLE 1 (No. 63)

Ex. Nos. R Physicochemical properties etc. 393

powder MS(ESI)524[M + H]+ 394

powder MS(ESI)512[M + H]+ 395

powder MS(ESI)455[M + H]+ 396

powder MS(ESI)554[M + H]+ 397

powder MS(ESI)524[M + H]+ 398

powder MS(ESI)510[M + H]+ 399

powder MS(ESI)524[M + H]+ Me: methyl group, Et: ethyl group, n-Bu: n-butyl group

TABLE 1 (No. 64)

Ex. Nos. R Physicochemical properties etc. 400

powder MS(ESI)538[M + H]+ 401

powder MS(ESI)550[M + H]+ 402

powder MS(ESI)554[M + H]+ 403

powder MS(ESI)560[M + H]+ 404

powder MS(ESI)588[M + H]+ 405

powder MS(ESI)587[M + H]+ Me: methyl group, Et: ethyl group, n-Bu: n-butyl group

TABLE 1 (No. 65)

Ex. Nos. R Physicochemical properties etc. 406

powder MS(ESI)506[M + H]+ 407

powder MS(ESI)638[M + H]+ 408

powder MS(ESI)534[M + H]+ 409

powder MS(ESI)532[M + H]+ 410

powder MS(ESI)664[M + H]+ 411

powder MS(ESI)490[M + H]+ Me: methyl group, Et: ethyl group

TABLE 1 (No. 66)

Ex. Nos. R Physicochemical properties etc. 412

powder MS(ESI)489[M + H]+ 413

powder MS(ESI)454[M + H]+ 414

powder MS(ESI)467[M + H]+ 415

powder MS(ESI)482[M + H]+ 416

powder MS(ESI)468[M + H]+ 417

powder MS(ESI)522[M + H]+ Me: methyl group, i-Pr: isopropyl group, t-Bu: tert-butyl group

TABLE 1 (No. 67)

Physicochemical Ex. Nos. R properties etc. 418

powder MS(ESI)501[M + H]+ 419

powder MS(ESI)515[M + H]+ 420

powder MS(ESI)469[M + H]+ 421

powder MS(ESI)550[M + H]+ 422

powder MS(ESI)466[M + H]+ 423

powder MS(ESI)496[M + H]+ 424

powder MS(ESI)470[M + H]+ Me: methyl group

TABLE 1 (No. 68)

Ex. Nos. R Physicochemical properties etc. 425

powder MS(ESI)488[M + H]+ 426

powder MS(ESI)516[M + H]+ 427

powder MS(ESI)514[M + H]+ 428

powder MS(ESI)500[M + H]+ 429

powder MS(ESI)554[M + H]+ 430

powder MS(ESI)510[M + H]+ 431

powder MS(ESI)508[M + H]+ Me: methyl group, Et: ethyl group

Examples 432 to 475

The corresponding materials are treated in the same manner as described in either one of the aforementioned Examples 1 to 5 followed by treating the product in the same manner as described in either one of the Examples 8 to 19 to give the compounds as shown in the following Table 2 (Nos. 1 to 9).

TABLE 2 (No. 1)

Ex. Nos. R Physicochemical properties etc. 432

powder MS(APCI)575/577[M + H]+ 433

oil MS(ESI)587[M + H + MeOH]+ 434

powder MS(ESI)562/564[M + H]+ Me: methyl group, n-Pr: n-propyl group

TABLE 2 (No. 2)

Ex. Nos. R Physicochemical properties etc. 435

powder MS(APCI)470/472[M + H]+ 436

powder MS(APCI)470/472[M + H]+ 437

powder MS(APCI)503/505[M + H]+ 438

powder MS(APCI)504/506[M + H]+ 439

powder MS(APCI)538/540[M + H]+ 440

powder MS(APCI)454/456[M + H]+ Me: methyl group, Et: ethyl group

TABLE 2 (No. 3)

Ex. Nos. R Physicochemical properties etc. 441

solid MS(APCI)524/526[M + H]+ 442

solid MS(APCI)560/562[M + H]+ 443

solid MS(APCI)589/591[M + H]+ 444

solid MS(APCI)553/555[M + H]+ 445

solid MS(APCI)553/555[M + H]+ 446

solid MS(APCI)582/584[M + H]+ Me: methyl group, Et: ethyl group, Boc: tert-butyloxtcarbonyl group

TABLE 2 (No. 4)

Ex. Nos. R Physicochemical properties etc. 447

solid MS(APCI)482/484[M + H]+ 448

powder MS(ESI)587 449

powder MS(ESI)573 450

powder MS(ESI)545 451

powder MS(ESI)539 452

powder MS(ESI)610 Me: methyl group

TABLE 2 (No. 5)

Ex. Nos. R Physicochemical properties etc. 453

powder MS(ESI)605 454

powder MS(ESI)581 455

powder MS(ESI)576 456

powder MS(ESI)541 457

powder MS(ESI)575 458

powder MS(ESI)598 Me: methyl group

TABLE 2 (No. 6)

Ex. Nos. R Physicochemical properties etc. 459

powder MS(ESI)594 460

powder MS(ESI)565 461

powder MS(ESI)530 462

powder MS(ESI)564 463

powder MS(ESI)580 464

powder MS(ESI)576 465

powder MS(ESI)552 Me: methyl group

TABLE 2 (No. 7)

Physicochemical Ex. Nos. R properties etc. 466

powder MS(ESI)546 467

powder MS(ESI)512 468

powder MS(ESI)546 Me: methyl group

TABLE 2 (No. 8)

Ex. Nos. R Physicochemical properties etc. 469

powder MS(SSI)474 470

powder MS(SSI)546 471

powder MS(SSI)546 472

powder MS(SSI)539 473

powder MS(SSI)539 474

powder MS(SSI)510 Me: methyl group, Et: ethyl group

TABLE 2 (No. 9)

Ex. Nos. R Physicochemical properties etc. 475

powder MS(APCI)507[M + H]+

Examples 436 to 499

The corresponding materials are treated in the same manner as described in Example 6 or 7 to give the compounds as shown in the following Table 3 (Nos. 1 to 6).

TABLE 3 (No. 1)

Ex. Nos. R Physicochemical properties etc. 476

powder MS(APCI)576/578[M + H]+ 477

powder MS(APCI)543/545[M + H]+ 478

powder MS(APCI)509/511[M + H]+ 479

powder MS(APCI)509/511[M + H]+ 480

powder MS(APCI)475/477[M + H]+ 481

powder MS(APCI)501[M + H]+ Me: methyl group

TABLE 3 (No. 2)

Ex. Nos. R R′ Physicochemical properties etc. 482

powder MS(APCI)517/519[M + H]+ Me: methyl group

TABLE 3 (No. 3)

Ex. Nos. R R′ Physicochemical properties etc. 483

powder MS(APCI)531/533[M + H]+ 484

powder MS(APCI)566/568[M + H]+ Me: methyl group, Et: ethyl group

TABLE 3 (No. 4)

Ex. Nos. R Physicochemical properties etc. 485

powder MS(APCI)562/564[M + H]+ 486

powder MS(APCI)590/592[M + H]+ 487

powder MS(APCI)588/590[M + H]+ 488

powder MS(APCI)604/606[M + H]+ 489

powder MS(APCI)510/512[M + H]+ 490

powder MS(APCI)506/508[M + H]+ 491

powder MS(APCI)553/555[M + H]+ Me:methyl group, Et:ethyl group

TABLE 3 (No. 5)

Ex. Nos. R Physicochemical properties etc. 492

powder MS(APCI)547/549[M + H]+ 493

powder MS(APCI)604/606[M + H]+ 494

powder MS(APCI)509/511[M + H]+ 495

powder MS(APCI)509/511[M + H]+ 496

powder MS(APCI)475/477[M + H]+ 497

powder MS(APCI)521/523[M + H]+ n-Bu:n-butyl group

TABLE 3 (No. 6)

Ex. Nos. R Physicochemical properties etc. 498

powder MS(APCI)509/511[M + H]+ 499

powder MS(ESI)518/520[M + H]+ Me: methyl group

Examples 500 to 507

The corresponding materials are treated in the same manner as described in the Example 6 or 7 followed by treating the product in the same manner as described in either one of the Examples 8 to 19 to give the compounds as shown in the following Table 4 (Nos. 1 to 2).

TABLE 4 (No. 1)

Ex. Nos. R R′ Physicochemical properties etc. 500

powder MS(APCI)539/541[M + H]+ 501

powder MS(APCI)489/491[M + H]+

TABLE 4 (No.2)

Physicochemical Ex. Nos. R properties etc. 502

powder MS(APCI)665/667 [M + H]+ 503

powder MS(APCI)596/598 [M + H]+ 504

powder MS(APCI)566/568 [M + H]+ 505

powder MS(APCI)580/582 [M + H]+ 506

powder MS(APCI)598/600 [M + H]+ 507

powder MS(APCI)643/645 [M + H]+ Me: methyl group

Examples 508 to 512

The corresponding materials are treated in the same manner as described in the Example 20 to give the compounds as shown in the following Table 5.

TABLE 5

Physicochemical Ex. Nos. R properties etc. 508

powder MS(APCI)468/470 [M + H]+ 509

powder MS(APCI)482/484 [M + H]+ 510

powder Ms(APCI)546/548 [M + H]+ 511

powder MS(APCI)540/542 [M + H]+ 512

powder MS(APCI)488/490 [M + H]+ Me: methyl group, Et: ethyl group

Example 513

To a solution of the compound obtained in Example 1 (64 mg) in water/methanol was added 6N HCl (21 μL) and the mixture was concentrated in vacuo to give (3R)-1[bis-(4-chlorophenyl)methyl]-3-[[4-(trifluoromethyloxy)benzoyl]amino]-pyrrolidine hydrochloride (68 mg, yield: 100%) as an amorphous powder.

MS(APCI) m/z; 509/511 [M+H]⁺

Example 514

(1) The compound obtained in Reference Example 13 (92 mg) was treated in the same manner as described in Example 6 to give (3S,4R)-1-[bis-(4-chlorophenyl)methyl]-3-ethyloxycarbonyl-4-[(4-cyanobenzoyl)amino]pyrrolidine (24 mg, yield: 15%) MS(APCI) m/z; 522/524 [M+H]⁺

(2) The compound obtained in the above step (1) (200 mg) and sodium borohydride (28.3 mg) were refluxed in tetrahydrofuran under heating. To the reaction mixture was added dropwise methanol (0.5 μL) over a period of 30 minutes and then the mixture was stirred at the same temperature for 1 hour. The reaction mixture was evaporated to remove solvent and thereto was added water and ethyl acetate. The organic layer was washed with water and a saturated brine and dried over magnesium sulfate. After removal of the desiccant, the filtrate was concentrated and the residue was purified by a column chromatography on silica gel (Solvent; n-hexane/ethyl acetate=1:1) to give (3S,4R)-1-[bis-(4-chlorophenyl)methyl]-3-hydroxymethyl-4-[(4-cyanobenzoyl)-amino]pyrrolidine (123.1 mg, yield: 67%).

MS(APCI) m/z; 480/482 [M+H]⁺

(3) The compound obtained in the above step (2) (60 mg) was dissolved in acentonitrile (7 mL) and thereto was added iodoethane (0.26 mL) and silver oxide (188 mg), and the mixture was stirred at room temperature for 3 days. The insoluble materials were removed by filtration and the filtrate was concentrated, and the residue was purified by a silica gel plate to give (3S,4R)-1-[bis-(4-chlorophenyl)methyl]-3-ethoxy-methyl-4-[(4-cyanobenzoyl)amino]pyrrolidine (13.2 mg, yield: 21%). MS(APCI) m/z; 508/510 [M+H]⁺

Examples 515 to 594

the corresponding starting materials were treated in the same manner as described in either one of Examples 1 to 5 and 21, and if required, further treated in the same manner as described in either one of Examples 8 to 19, 22 and 513 to give a compound as shown in the following Table 6.

TABLE 6 (No. 1)

Physicochemical properties Ex. Nos. R etc. 515

powder MS(APCI)511/513[M + H]+ 516

powder MS(APCI)461/463[M + H]+ 517

powder MS(APCI)493/495[M + H]+ 518

powder MS(APCI)503/505/507 [M + H]+ 519

powder MS(APCI)468/470[M + H]+ 520

powder MS(APCI)491/493[M + H]+ 521

powder MS(APCI)494/496[M + H]+

TABLE 6 (No. 2)

Ex. Nos. R Physicochemical properties etc. 522

powder MS(APCI)451/453[M + H]+ 523

powder MS(ESI)470[M + H]+

TABLE 6 (No. 3)

Physicochemical Ex. Nos. R R ′ properties etc. 524

powder MS(APCI)521 [M + H]+ 525

powder MS(APCI)535 [M + H]+ 526 H

powder MS(ESI)475 [M + H]+ 527 H

powder MS(APCI)493 [M + H]+ 528

powder MS(ESI)519 [M + H]+ 529

powder MS(ESI)537 [M + H]+ Me: methyl group, Et: ethyl group

TABLE 6 (No 4)

Ex. Nos. R Physicochemical properties etc. 530

powder MS(APCI)498[M + H]+ 531

powder MS(APCI)516[M + H]+ i-Pr: isopropyl group

TABLE 6 (No. 5)

Ex. Nos. R R′ Physicochemical properties etc. 532

powder MS(ESI)594[M + H]+ 533

powder MS(APCI)466/468[M + H]+ 534

powder MS(APCI)484/486[M + H]+ 535

powder MS(APCI)489/491[M + H]+ 536

powder MS(APCI)503/505[M + H]+ 537

powder MS(APCI)480/482[M + H]+ Me: methyl group, Et: ethyl group

TABLE 6 (No. 6)

Ex. Nos. R R′ Physicochemical properties etc. 538

powder MS(APCI)494/496[M + H]+ 539

powder MS(APCI)498/500[M + H]+ 540

powder MS(APCI)512/514[M + H]+ 541*

powder MS(APCI)544/546[M + H]+ 542

powder MS(ESI)508[M + H]+ 543*

powder MS(APCI)494/496[M + H]+ 544

powder MS(ESI)535[M + H]+ *hydrochloride Me: methyl group, Et: ethyl group, n-Pr: n-propyl group

TABLE 6 (No. 7)

Ex. Nos. R R′ Physicochemical properties etc. 545

powder MS(ESI)533[M + H]+ 546

powder MS(ESI)567[M + H]+ 547

powder MS(ESI)585[M + H]+ 548

powder MS(ESI)509[M + H]+ 549

powder MS(ESI)526[M + H]+ 550

powder MS(ESI)542[M + H]+ 551

powder MS(ESI)553[M + H]+ Me: methyl group, n-Pr: n-propyl group

TABLE 6 (No. 8)

Ex. Nos. R Physicochemical properties etc. 552

powder MS(ESI)441[M + H]+ 553

powder MS(ESI)494[M + H]+ 554

powder MS(ESI)450[M + H]+ 555

powder MS(APCI)484/486[M + H]+ 556

powder MS(ESI)482[M + H]+ 557

powder MS(ESI)502[M + H]+ 558

powder MS(ESI)485[M + H]+ 559

powder MS(ESI)459[M + H]+

TABLE 6 (No. 9)

Ex. Nos. R R′ Physicochemical properties etc. 560 CN

powder MS(ESI)484[M + H]+ 561 CN

powder MS(ESI)468[M + H]+ 562 CN

powder MS(ESI)486[M + H]+ 563 Cl

powder MS(ESI)434[M + H]+ 564 Cl

powder MS(ESI)443[M + H]+ 565 Cl

powder MS(ESI)493[M + H]+ 566 Cl

powder MS(ESI)477[M + H]+

TABLE 6 (No. 10)

Ex. Nos. R R′ Physicochemical properties etc. 567 Cl

powder MS(ESI)478[M + H]+ 568 Cl

powder MS(ESI)452[M + H]+ 569 OMe

powder MS(ESI)473[M + H]+ Me: methyl group

TABLE 6 (No. 11)

Ex. Nos. R Physicochemical properties etc. 570

powder MS(ESI)446[M + H]+ 571

powder MS(ESI)496[M + H]+ 572

powder MS(ESI)480[M + H]+ 573

powder MS(ESI)498[M + H]+ 574

powder MS(ESI)455[M + H]+ Me: methyl group

TABLE 6 (No. 12)

Ex. Nos. R R′ Physicochemical properties etc. 575

powder MS(ESI)480[M + H]+ 576

powder MS(ESI)530[M + H]+ 577

powder MS(ESI)514[M + H]+ 578

powder MS(ESI)485[M + H]+ 579

powder MS(ESI)494[M + H]+ 580

powder MS(ESI)544[M + H]+ 581

powder MS(ESI)528[M + H]+ Me: methyl group, Et: ethyl group

TABLE 6 (No. 13)

Ex. Nos. R R′ Physicochemical properties etc. 582

powder MS(ESI)546[M + H]+ 583

powder MS(ESI)529[M + H]+ 584

powder MS(ESI)503[M + H]+ 585

powder MS(ESI)489[M + H]+ 586

powder MS(ESI)544[M + H]+ Me: methyl group, Et: ethyl group

TABLE 6 (No. 14)

Ex. Physico- Nos. R R′ chemical properties etc. 587

powder MS(ESI)544[M + H]+ Me: methyl group

TABLE 6 (No. 15)

Ex. Nos. R Physicochemical properties etc. 588

powder MS(APCI)550[M + H]+

TABLE 6 (No. 16)

Ex. Nos. R Physicochemical properties etc. 598

powder MS(ESI)503[M + H]+ 590

powder MS(APCI)484/486[M + H]+ 591

powder MS(APCI)484/486[M + H]+ Et: ethyl group

TABLE 6 (No. 17)

Ex. Nos. R Physicochemical properties etc. 592

powder MS(APCI)500/502[M + H]+ 593

powder MS(APCI)500/502[M + H]+ 594*

powder MS(APCI)500/502[M + H]+ *hydrochloride

Examples 95 to 619

The corresponding starting materials were treated in the same manner as described in either one of Examples 6 and 7, and if required, further treated in the same manner as described in either one of Examples 8 to 19, 22 and 514 to give a compound as shown in the following Table 7.

TABLE 7 (No. 1)

Ex. Nos. R Physicochemical properties etc. 595

powder MS(APCI)477[M + H]+ 596

powder MS(APCI)461[M + H]+

TABLE 7 (No. 2)

Ex. Nos. R R′ Physicochemical properties etc. 597 Cl

powder MS(APCI)558/560[M + H]+ 598 CN

powder MS(APCI)549[M + H]+ Et: ethyl group

TABLE 7 (No. 3)

Ex. Nos. R R′ Physicochemical properties etc. 599 —CN

powder MS(APCI)485/487[M + H]+ 600 —CN

powder MS(APCI)499/501[M + H]+ Me: methyl group, Et: ethyl group

TABLE 7 (No. 4)

Ex. Nos. R Physicochemical properties etc. 601

powder MS(APCI)518[M + H]+ 602

powder MS(APCI)498/500[M + H]+ 603

powder MS(APCI)498/500[M + H]+ 604

powder MS(APCI)536[M + H]+ 605

powder MS(APCI)486[M + H]+ 606

powder MS(APCI)498[M + H]+ Me: methyl group

TABLE 7 (No. 5)

Ex. Nos. R Physicochemical properties etc. 607

powder MS(APCI)475[M + H]+ 608

powder MS(APCI)484/486[M + H]+

TABLE 7 (No. 6)

Ex. Nos. R Physicochemical properties etc. 609

powder MS(APCI)519/521[M + H]+ 610

powder MS(APCI)505/507[M + H]+ 611

powder MS(APCI)524[M + H]+ 612

powder MS(APCI)534[M + H]+ 613

powder MS(APCI)543/545[M + H]+ 614

powder MS(APCI)514/516[M + H]+ 615

powder MS(APCI)514/516[M + H]+ Me: methyl group, i-Pr: isopropyl group

TABLE 7 (No. 7)

Ex. Nos. R Physicochemical properties etc. 616

powder MS(APCI)502[M + H]+ 617

powder MS(APCI)514[M + H]+ 618

powder MS(APCI)552[M + H]+ 619

powder MS(APCI)518/520[M + H]+ Me: methyl group

Examples 620 to 631

The corresponding starting materials were treated in the same manner as described in one of Examples 1 to 5 to give a compound as shown in the following Table 8.

TABLE 8 (No. 1)

Ex. Nos. R² R′ Physicochemical properties etc. 620

powder MS(APCI)468/470[M + H]+ 621

powder MS(APCI)459/461[M + H]+ 622

powder MS(APCI)461/463[M + H]+ 623

n-Bu powder MS(APCI)396/398[M + H]+ n-Bu: n-butyl group

TABLE 8 (No. 2)

Ex. Nos. R² R′ Physicochemical properties etc. 624 —Cl

powder MS(APCI)465/467[M + H]+ 625 —CN

powder MS(APCI)456/468[M + H]+ 626 —Cl

powder MS(APCI)499/501[M + H]+ 627 —CN

powder MS(APCI)490/492[M + H]+

TABLE 8 (No. 3)

Ex. Nos. R Physicochemical properties etc. 628

powder MS(APCI)475[M + H]+ 629

powder MS(APCI)475[M + H]+

TABLE 8 (No. 4)

Ex. Nos. R Physicochemical properties etc. 630

powder MS(APCI)484/486[M + H]+ 631

powder MS(APCI)451/453[M + H]+ Me: methyl group

Examples 632 to 708

The corresponding starting materials were treated in the same manner as described in either one of Examples 6 and 7 to give a compound as shown in the following Table 9.

TABLE 9 (No. 1)

Ex. Nos. R Physicochemical properties etc. 632

powder MS(APCI)497[M + H]+ 633

powder MS(APCI)481[M + H]+ 634

powder MS(APCI)438[M + H]+ 635

powder MS(APCI)477/449[M + H]+ Me: methyl group

TABLE 9 (No. 2)

Ex. Nos. R Physicochemical properties etc. 636

powder MS(APCI)508[M + H]+ 637

powder MS(APCI)465[M + H]+ 638

powder MS(APCI)474/476[M + H]+ i-Pr: isopropyl group

TABLE 9 (No. 3)

Ex. Nos. R Physicochemical properties etc. 639

powder MS(APCI)459/461[M + H]+ 640

powder MS(APCI)502/504[M + H]+

TABLE 9 (No. 4)

Ex. Nos. R Physicochemical properties etc. 641

powder MS(APCI)451[M + H]+ 642

powder MS(APCI)510[M + H]+ 643

powder MS(APCI)494[M + H]+ 644

powder MS(APCI)460/462[M + H]+ Et: ethyl group

TABLE 9 (No. 5)

Physico- Ex. Nos. R R′ chemical properties etc. 645 —CN

powder MS(APCI)466[M + H]+ 646 —CN

powder MS(APCI)525[M + H]+ 647 —CN

powder MS(APCI)509[M + H]+ 648 —CN

powder MS(APCI)475/ 477[M + H]+ 649 —Cl

powder MS(APCI)475/ 477[M + H]+ 650 —Cl

powder MS(APCI)534/ 536[M + H]+ 651 —Cl

powder MS(APCI)518/ 520[M + H]+ 652 —Cl

powder MS(APCI)484/ 486[M + H]+ i-Pr: isopropyl group

TABLE 9 (No. 6)

Ex. Nos. R² R Physicochemical properties etc. 653

powder MS(APCI)461/463[M + H]+ 654

powder MS(APCI)503/505[M + H]+ 655

powder MS(APCI)470/472[M + H]+ 656

powder MS(APCI)515/517[M + H]+ 657

powder MS(APCI)529/531[M + H]+ Me: methyl group

TABLE 9 (No. 7)

Ex. Physicochemical Nos. R R′ properties etc. 658 —CN

powder MS(APCI)491 [M + H]+ 659 —CN

powder MS(APCI)550 [M + H]+ 660 —CN

powder MS(APCI) 500/502[M + H]+ 661 —Cl

powder MS(APCI) 500/502[M + H]+ 662 —Cl

powder MS(APCI) 559/561[M + H]+ 663 —Cl

powder MS(APCI) 509/511[M + H]+ 664 —CN

powder MS(APCI)534 [M + H]+ 665 —Cl

powder MS(APCI) 543/545[M + H]+

TABLE 9 (No. 8)

Ex. Physicochemical Nos. R R′ properties etc. 666 —CN

powder MS(APCI) 459/461[M + H]+ 667 —CN

powder MS(APCI) 518/520[M + H]+ 668 —CN

powder MS(APCI) 468/470[M + H]+ 669 —Cl

powder MS(APCI) 468/470[M + H]+ 670 —Cl

powder MS(APCI) 527/529[M + H]+ 671 —CN

powder MS(APCI) 502/504[M + H]+ 672 —Cl

powder MS(APCI) 511/513[M + H]+

TABLE 9 (No. 9)

Ex. Physicochemical Nos. R properties etc. 673

powder MS(APCI) 518/520[M + H]+ 674

powder MS(APCI) 459/461[M + H]+ 675

powder MS(APCI) 468/470[M + H]+ 676

powder MS(APCI) 502/504[M + H]+

TABLE 9 (No. 10)

Ex. Physicochemical Nos. R properties etc. 677

powder MS(APCI) 493[M + H]+ 678

powder MS(APCI) 421[M + H]+ 679

powder MS(APCI) 475/477[M + H]+ 680

powder MS(APCI) 459/461[M + H]+ 681

powder MS(APCI) 453[M + H]+ 682

powder MS(APCI) 447/449[M + H]+ 683

powder MS(APCI) 449[M + H]+ 684

powder MS(APCI) 465[M + H]+ Me: methyl group

TABLE 9 (No. 11)

Ex. Physicochemical Nos. R properties etc. 685

powder MS(APCI) 466[M + H]+ 686

powder MS(APCI) 473[M + H]+ 687

powder MS(APCI) 514[M + H]+ 688

powder MS(APCI) 476[M + H]+ 689

powder MS(APCI) 446/448[M + H]+ 690

powder MS(APCI) 496[M + H]+ 691

powder MS(APCI) 484[M + H]+ Me: methyl group, i-Pr: isopropyl group

TABLE 9 (No. 12)

Ex. Physicochemical Nos. R properties etc. 692

powder MS(APCI) 475/477[M + H]+ 693

powder MS(APCI) 455[M + H]+ 694

powder MS(APCI) 480[M + H]+ 695

powder MS(APCI) 509[M + H]+ 696

powder MS(APCI) 508[M + H]+ Me: methyl group, i-Pr: isopropyl group

TABLE 9 (No. 13)

Ex. Physicochemical Nos. R properties etc. 697

powder MS(APCI) 450[M + H]+ 698

powder MS(APCI) 458[M + H]+ 699

powder MS(APCI) 466[M + H]+ 700

powder MS(APCI) 433[M + H]+ 701

powder MS(APCI) 475/477[M + H]+ 702

powder MS(APCI) 443[M + H]+ 703

powder MS(APCI) 442/444 [M + H]+. Me: methyl group, i-Pr: isopropyl group

TABLE 9 (No. 14)

Ex. Physicochemical Nos. R properties etc. 704

powder MS(APCI) 519[M + H]+ 705

powder MS(APCI) 485/487[M + H]+ 706

powder MS(APCI) 422[M + H]+ 707

powder MS(APCI) 457[M + H]+ 708

powder MS(APCI) 423[M + H]+ Me: methyl group

Example 709

The corresponding materials were treated in the same manner as described in Example 8 to give (3R)-1-[(4-chlorophenyl)(2-cyanophenyl)methyl]-3-[[4-(trifluoro-methoxy)benzoyl]amino]pyrrolidine as a powder. MS(APCI) m/z: 500/502 [M+H]⁺

Example 710

The compound obtained in Reference Example 21 (50 mg) and dimethylamine were treated in the same manner as described in Example 19(2) to give (3R)-1-[(4-cyanophenyl)(4-dimethylcarbamoylphenyl)methyl]-3-[[(4-trifluoromethoxy)benzoyl]amino]pyrrolidine as a powder. MS(APCI) m/z: 546/548 [M+H]⁺

Example 711

To a solution of (3R)-1-[(4-methylthiophenyl)(4-cyanophenyl)methyl]-3-[(4-cyanobenzoyl)amino]pyrrolidine (45.3 mg) in methylene chloride (2 mL) was added trifluoroacetic acid (31 μL) under ice-cooling and the mixture was stirred at room temperature or 30 minutes. Thereto was added m-chloroperbenzoic acid (23 mg) under ice-cooling and the mixture was stirred at the same temperature for 1 hour and then stirred at room temperature for 4 hours. To the reaction mixture was added an aqueous saturated sodium hydrogen carbonate solution and the organic layer was extracted by a diatomaceous earth column (Chem Elut; VARIAN Inc.). The extract was concentrated in vacuo and the resultant crude product was purified by a column chromatography on silica gel (solvent; chloroform/methanol=98:2→90:10). The resultant product was dissolved in t-buthanol and lyophilized to give (3R)-1-[(4-cyanophenyl)-(4-methylsulfinylphenyl)methyl]-3-[(4-cyanobenzoyl)amino]pyrrolidine (42.5 mg, yield: 91%) as a powder. MS(APCI) m/z: 469 [M+H]⁺

Example 712

To a solution of (3R)-1-[(4-methylthiophenyl)(4-cyanophenyl)methyl]3-[(4-cyanobenzoyl)amino]pyrrolidine (45.3 mg) in methylene chloride (2 mL) was added trifluoroacetic acid (31 μL) under ice-cooling and the mixture was stirred at room temperature for 30 minutes. Thereto was added m-chloroperbenzoic acid (46 mg) under ice-cooling and the mixture was stirred at the same temperature for 1 hour and then stirred at room temperature for 2 hours. To the reaction mixture was added an aqueous saturated sodium hydrogen carbonate solution and the organic layer was extracted by a diatomaceous earth column (Chem Elut). The extract was concentrated in vacuo and the resultant crude product was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=40:60→60:40). The resultant product was dissolved in t-buthanol and lyophilized to give (3R)-1-[(4-cyanophenyl)(4-methylsulfonylphenyl)-methyl]-3-[(4-cyanobenzoyl)amino]pyrrolidine (27.4 mg, yield: 57%) as a powder.

MS(APCI) m/z: 485 [M+H]⁺

Example 713

To a solution of [(4-chlorophenyl)(4-chloro-2-methylphenyl)]methanol (40.1 mg) in methylene chloride (0.65 mL) was added phosphorus tribromide (20 μL) and the mixture was stirred at room temperature overnight. To the reaction mixture was added water and chloroform and the mixture was stirred. The organic layer was extracted by a diatomaceous earth column (Chem Elut) and concentrated in vacuo. To the resultant residue was added diisopropylethylamine (105 μL) and acetonitrile (1 mL) and the mixture was refluxed under heating for 2 days. After cooling to room temperature, to the reaction mixture was added water and ethyl acetate and the organic layer was separated and concentrated in vacuo. The resultant crude product was purified by HPLC (XTerra PrepMS C18 column, solvent; water/methanol=1:1→5:95). The resultant product was dissolved in t-buthanol and lyophilized to give (3R)-1-[(4-chlorophenyl)(4-chloro-2-methylphenyl)methyl]-3-[(4-cyanobenzoyl)amino]pyrrolidine (37.3 mg, yield: 54%) as a powder. MS(APCI) m/z: 464/466 [M+H]⁺

Examples 714 to 716

The corresponding starting materials were treated in the same manner as described in Example 712 to give the compound as shown in the following Table 10.

TABLE 10

Physicochemical Ex. Nos. R¹ R² R″ properties etc. 714

—CN powder MS(APCI) 528[M + H]+ 715

—CN powder MS(APCI) 544[M + H]+ 716

—CN powder MS(APCI) 519[M + H]+ Me: methyl group, i-Pr: isopropyl group

Example 717

The corresponding starting materials were treated in the same manner as described in Example 1 to give the compound as shown in the following Table 11.

TABLE 11

Ex. Physicochemical Nos. R properties etc. 717

powder MS(APCI) 417/419[M + H]+

Examples 718 to 751

The corresponding starting materials were treated in the same manner as described in either one of Examples 6 and 7 to give the compounds as shown in the following Table 12.

TABLE 12 (No. 1)

Ex. Nos. R Physicochemical properties etc. 718

powder MS(APCI)487[M + H]+ 719

powder MS(APCI)464[M + H]+ 720

powder MS(APCI)442/444[M + H]+ Me: methyl group, i-Pr: isopropyl group

TABLE 12 (No. 2)

Ex. Nos. R Physicochemical properties etc. 721

powder MS(APCI)493[M + H]+ 722

powder MS(APCI)460/462[M + H]+ 723

powder MS(ESI)484[M + H]+ 724

powder MS(ESI)469[M + H]+ 725

powder MS(ESI)483[M + H]+ 726

powder MS(ESI)470[M + H]+ 727

powder MS(ESI)506[M + H]+ Et: ethyl group, i-Pr: isopropyl group

TABLE 12 (No. 3)

Ex. Nos. R Physicochemical properties etc. 728

powder MS(ESI)500[M + H]+ 729

powder MS(ESI)497[M + H]+ 730

powder MS(ESI)515[M + H]+ 731

powder MS(ESI)509[M + H]+ 732

powder MS(ESI)479[M + H]+ 733

powder MS(ESI)465[M + H]+ 734

powder MS(ESI)531[M + H]+ Me: methyl group, Et: ethyl group

TABLE 12 (No. 4)

Ex. Nos. R Physicochemical properties etc. 735

powder MS(ESI)549[M + H]+ 736

powder MS(ESI)543[M + H]+ 737

powder MS(ESI)513[M + H]+ 738

powder MS(ESI)499[M + H]+ Me: methyl group, Et: ethyl group

TABLE 12 (No. 5)

Ex. Nos. R Physicochemical properties etc. 739

powder MS(ESI)452[M + H]+ 740

powder MS(ESI)488[M + H]+ 741

powder MS(ESI)482[M + H]+ 742

powder MS(ESI)479[M + H]+ 743

powder MS(ESI)497[M + H]+ 744

powder MS(ESI)491[M + H]+ 745

powder MS(ESI)461[M + H]+ Me: methyl group, Et: ethyl group

TABLE 12 (No. 6)

Ex. Nos. R Physicochemical properties etc. 746

powder MS(ESI)447[M + H]+ 747

powder MS(ESI)513[M + H]+ 748

powder MS(ESI)531[M + H]+ 749

powder MS(ESI)525[M + H]+ 750

powder MS(ESI)495[M + H]+ 751

powder MS(ESI)481[M + H]+ Me: methyl group, Et: ethyl group

TABLE 12 (No. 7)

Ex. Nos. R Physicochemical properties etc. 752

powder MS(APCI)467[M + H]+ 753

powder MS(APCI)439[M + H]+ 754

powder MS(APCI)476/478[M + H]+ 755

powder MS(APCI)510[M + H]+ 756

powder MS(APCI)523[M + H]+ 757

powder MS(APCI)458[M + H]+ 758

powder MS(APCI)461/463[M + H]+ Me: methyl group, Et: ethyl group, i-Pr: isopropyl group

TABLE 12 (No. 8)

Ex. Nos. R Physicochemical properties etc. 759

powder MS(APCI)495[M + H]+ 760

powder MS(APCI)452[M + H]+ 761

powder MS(APCI)470[M + H]+ Me: methyl group

TABLE 12 (No. 9)

Ex. Nos. R Physicochemical properties etc. 762

powder MS(APCI)457[M + H]+ 763

powder MS(APCI)494/496[M + H]+ 764

powder MS(APCI)528[M + H]+ 765

powder MS(APCI)485[M + H]+ i-Pr: isopropyl group

TABLE 12 (No. 10)

Ex. Nos. R Physicochemical properties etc. 766

powder MS(APCI)473[M + H]+ i-Pr: isopropyl group

Examples 767 to 769

The corresponding starting materials were treated in the same manner as described in Examples 3 to give a compound as shown in the following Table 13.

TABLE 13

Ex. Nos. R Physicochemical properties etc. 767

powder MS(APCI)494[M + H]+ 768

powder MS(APCI)496[M + H]+ 769

powder MS(APCI)534/536[M + H]+ Me: methyl group, Et: ethyl group

Examples 770 to 786

The corresponding starting materials were treated in the same manner as described in Example 6 to give the compounds as shown in the following Table 14.

TABLE 14 (No. 1)

Ex. Nos. R Physicochemical properties etc. 770

powder MS(APCI)490[M + H]+ 771

powder MS(APCI)472[M + H]+ i-Pr: isopropyl group

TABLE 14 (No. 2)

Ex. Nos. R R′ Physicochemical properties etc. 772 Me

powder MS(APCI)471[M + H]+ 773 Me

powder MS(APCI)489[M + H]+ 774 Me

powder MS(APCI)472[M + H]+ 775 Et

powder MS(APCI)485[M + H]+ 776 Et

powder MS(APCI)503[M + H]+ 777 Et

powder MS(APCI)486[M + H]+ Me: methyl group, Et: ethyl group, i-Pr: isopropyl group

TABLE 14 (No. 3)

Ex. Nos. R Physicochemical properties etc. 778

powder MS(APCI)499[M + H]+ 779

powder MS(APCI)517[M + H]+ 780

powder MS(APCI)500[M + H]+ i-Pr: isopropyl group

TABLE 14 (No. 4)

Ex. Nos. R R′ Physicochemical properties etc. 781

powder MS(APCI)507[M + H]+ 782

powder MS(APCI)525[M + H]+ 783

powder MS(APCI)508[M + H]+ 784 Et

powder MS(APCI)453[M + H]+ 785 Et

powder MS(APCI)471[M + H]+ Et: ethyl group, i-Pr: isopropyl group

TABLE 14 (No. 5)

Ex. Nos. R Physicochemical properties etc. 786

powder MS(APCI)502[M + H]+

Examples 787 to 791

The corresponding starting materials were treated in the same manner as described in Example 1 to give the compounds as shown in the following Table 15.

TABLE 15 (No. 1)

Ex. Nos. R Physicochemical properties etc. 787

powder MS(APCI)528[M + H]+ 788

powder MS(APCI)537[M + H]+ Me: methyl group, i-Pr: isopropyl group

TABLE 15 (No. 2)

Ex. Nos. R Physicochemical properties etc. 789

powder MS(APCI)500[M + H]+ 790

powder MS(APCI)518[M + H]+ 791

powder MS(APCI)501[M + H]+ i-Pr: isopropyl group

Examples 792 to 829

The corresponding starting materials were treated in the same manner as described in Example 6 to give the compounds as shown in the following Table 16.

TABLE 16 (No. 1)

Ex. Physico- Nos. R¹ chemical properties etc. 792

powder MS(APCI)494[M + H]+ 793

powder MS(APCI)452[M + H]+ 794

powder MS(APCI)480[M + H]+ 795

powder MS(APCI)494[M + H]+ 796

powder MS(APCI)478[M + H]+ 797

powder MS(APCI)464[M + H]+ 798

powder MS(APCI)478[M + H]+ Me: methyl group, Et: ethyl group, n-Pr: n-propyl group, i-Pr: isopropyl group

TABLE 16 (No. 2)

Ex. Physico- Nos. R¹ chemical properties etc. 799

powder MS(APCI)478[M + H]+ 800

powder MS(APCI)492[M + H]+ 801

powder MS(APCI)478[M + H]+ 802

powder MS(APCI)494[M + H]+ 803

powder MS(APCI)506[M + H]+ Me: methyl group

TABLE 16 (No. 3)

Ex. Physicochemical Nos. R¹ properties etc. 804

powder MS(APCI)476[M + H]+ 805

powder MS(APCI)512[M + H]+ 806

powder MS(APCI)470[M + H]+ 807

powder MS(APCI)498[M + H]+ 808

powder MS(APCI)512[M + H]+ 809

powder MS(APCI)496[M + H]+ 810

powder MS(APCI)482[M + H]+ Me: methyl group, Et: ethyl group, i-Pr: isopropyl group

TABLE 16 (No. 16)

Ex. Physicochemical Nos. R¹ properties etc. 811

powder MS(APCI)496[M + H]+ 812

powder MS(APCI)496[M + H]+ 813

powder MS(APCI)510[M + H]+ 814

powder MS(APCI)496[M + H]+ 815

powder MS(APCI)512[M + H]+ 816

powder MS(APCI)524[M + H]+ Me: methyl group, n-Pr: n-propyl group

TABLE 16 (No. 5)

Ex. Physicochemical Nos. R¹ properties etc. 817

powder MS(APCI)459[M + H]+ 818

powder MS(APCI)495[M + H]+ 819

powder MS(APCI)453[M + H]+ 820

powder MS(APCI)481[M + H]+ 821

powder MS(APCI)495[M + H]+ 822

powder MS(APCI)479[M + H]+ 823

powder MS(APCI)465[M + H]+ Me: methyl group, Et: ethyl group, i-Pr: isopropyl group

TABLE 16 (No. 6)

Ex. Physicochemical Nos. R¹ properties etc. 824

powder MS(APCI)479[M + H]+ 825

powder MS(APCI)479[M + H]+ 826

powder MS(APCI)493[M + H]+ 827

powder MS(APCI)479[M + H]+ 828

powder MS(APCI)495[M + H]+ 829

powder MS(APCI)507[M + H]+ Me: methyl group, n-Pr: n-propyl group

Reference Example 1

(1) To a suspension of 4-hydroxybenzaldehyde (2.0 g), dimethylaminoethyl chloride hydrochloride (2.83 g), dimethylformamide (8 mL) in diisopropylether (1 mL) is added potassium carbonate (5.53 g) and the mixture was stirred at 60° C. overnight. To the reaction mixture was added water and the mixture was extracted with ethyl acetate (×2). The organic layer is concentrated in vacuo and the resultant crude product was purified by a column chromatography on silica gel (solvent; chloroform/methanol=100:0→90:10) to give 4-[2-(dimethylamino)ethoxy]benzaldehyde (674 mg, yield: 21%) as an oil.

MS(APCI) m/z; 194 [M+H]⁺

(2) To a solution of 1.0M 4-chlorophenylmagnesium bromide in diethylether (2 mL) was added a solution of the compound obtained in the above step (1) (386.5 mg) in tetrahydrofuran (4 mL) under nitrogen gas atmosphere and cooling in dry ice/acetone bath and the mixture is stirred at room temperature overnight. To the reaction mixture was added water and the mixture was extracted with ethyl acetate (×2). The organic layer was concentrated in vacuo and the resultant crude product was purified by a flash column chromatography on NH-silica gel (Chromatorex NH-silica gel, solvent; hexane/ethyl acetate=1:1→0:1) to give (4-chlorophenyl)[4-[2-(dimethylamino)-ethoxy]phenyl]methanol (208 mg, yield: 34%) as an oil.

MS(APCI) m/z; 306/308 [M+H]⁺

Reference Example 2

(1) To a solution of bis(4-hydroxyphenyl)ketone (1.0 g) in dimethylformamide (10 mL) was added successively potassium carbonate (2.54 g) and isopropyl iodide (1.40 mL) and the mixture was stirred at room temperature for 18 hours. To the reaction mixture was added water and the mixture is extracted with ethyl acetate (×2). The organic layer was concentrated in vacuo and the resultant crude product was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=95:5→60:40) to give bis(4-isopropyloxyphenyl)ketone (1.33 g, yield: 96%) as a powder.

MS(APCI) m/z; 299 [M+H]⁺

(2) To a solution of the compound obtained in the above step (1) (1.33 g) in ethanol (18 μL) and tetrahydrofuran (2 mL) was added sodium borohydride (235 mg) and the mixture was stirred at room temperature for 18 hours. After concentrating the reaction mixture, thereto was added ethyl acetate and water, and the mixture was extracted with ethyl acetate (×2). The organic layer was concentrated in vacuo and the resultant crude product was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=95:5→40:60) to give bis(4-isopropyloxyphenyl)methanol (1.30 g, yield: 97%) as an oil.

MS(APCI) m/z; 283 [M+H]⁺

Reference Example 3

(1) To a solution of 4-bromobenzylalcohol (9.98 g) and triethylamine (11.2 μL) in ethyl acetate (100 mL) was added dropwise methanesulfonyl chloride (7.35 g) under nitrogen gas atmosphere and ice-cooling and the mixture was stirred under ice-cooling for 1 hour. To the reaction mixture was added water and the mixture was extracted with ethyl acetate (×2). After washing successively with water and a saturated brine, the organic layer was dried over anhydrous magnesium sulfate. After evaporation to remove solvent, the resultant crude product was triturated in ethyl acetate/hexane to 4-bromobenzyl methanesulfonate (13.54 g, yield: 91%) as crystals.

MS(EI) m/z; 264/266 [M+H]⁺

(2) A suspension of the compound obtained in the above step (1) (1.2 g) in methanol was stirred at 85° C. for 4 hours. The reaction mixture was concentrated in vacuo. To the resultant residue was water and the mixture was extracted with ethyl acetate (×2). The organic layer was concentrated in vacuo and the resultant crude product was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=80:20→60:40) to give 4-bromobenzylmethylether (0.76 g, yield: 83%) as an oil.

MS(APCI) m/z; 200/202 [M+H]⁺

(3) To a solution of the compound obtained in the above step (2) (515 mg) in tetrahydrofaran (4 mL) was added dropwise 1.59M butyl lithium-hexane solution (1.61 mL) under nitrogen gas atmosphere and cooling in dry ice/acetone bath and the mixture was stirred for 10 minutes. Thereto was added a solution of 4-chlorobenzaldehyde (360 mg) in tetrahydrofuran (1 mL) and the mixture was stirred at room temperature overnight. To the reaction mixture was added water and the mixture was extracted with ethyl acetate (×2). The organic layer was concentrated in vacuo and the resultant crude product was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=80:20→60:40) to give (4-chlorophenyl)[4-(methoxymethyl)phenyl]methanol (459 mg, yield: 68%) as an oil.

MS(APCI) m/z; 247/202 [M+H−H₂O]⁺

Reference Example 4

(1) To a suspension of bis-(4-carboxyphenyl)ketone (5.0 g) in methylene chloride (100 mL) was added oxalyl chloride (3.4 μL) and dimethylformamide (200 μL) under nitrogen gas atmosphere and cooling in dry ice/acetone bath and the mixture was stirred at room temperature for 4 hours. To the reaction mixture was added tetrahydrofuran (50 mL) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was evaporated to remove solvent and to the residue was added successively tetrahydrofuran (100 mL), triethylamine (7.75 mL) and tert-butylamine (4.86 mL) and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture was added water and the resultant crystals were collected by filtration to give bis[4-(tert-butylcarbamoyl)phenyl]ketone (6.44 g, yield: 92%) as crystals.

MS(EI) m/z; 381 [M+H]⁺

(2) To a suspension of the compound obtained in the above step (1) (2.9 g), 2-propanol (15.2 mL) and water (0.9 mL) was added sodium borohydride (232 mg) and the mixture was stirred at 85° C. for 30 minutes. After cooling to room temperature, thereto was added water and the resultant crystals were collected by filtration to give bis[4-(tert-butylcarbamoyl)phenyl]methanol (2.85 g, yield: 97%) as crystals.

MS(APCI) m/z; 383 [M+H]⁺

(3) A solution of the compound obtained in the above step (2) (4.96 g) in thionyl chloride (40 mL) was refluxed under heating for 5 hours. The reaction mixture was concentrated in vacuo and thereto was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and a saturated brine, dried over anhydrous magnesium sulfate and evaporated in vacuo to give chloro[bis-(4-cyanophenyl)]methane (3.59 g, yield: 100%) as an oil.

Reference Example 5

(1) To a solution of 4-cyanobenzaldehyde (3.93 g) in tetrahydrofaran was added dropwise 1.0M 4-chlorophenylmagnesium bromide-diethylether (30 mL) under nitrogen gas atmosphere and cooling in dry ice/methanol bath and the mixture was stirred at the same temperature for 10 minutes. To the reaction mixture was added 10% HCl solution and the aqueous layer was extracted with ethyl acetate (×2). The organic layer was washed with a saturated brine, dried over magnesium sulfate and concentrated in vacuo. To the resultant crude product was added diisopropyl ether and the resultant solid materials were collected by filtration to give (4-chlorophenyl)(4-cyanophenyl)methanol (6.98 g, yield: 96%) as a pale yellow solid.

MS(APCI) m/z; 268, 280 [M+Cl]⁺

(2) A mixture of the compound obtained in the above step (1) (12.4 g) and thionyl chloride (30 mL) was refluxed under heating for 3 hours and the reaction mixture was concentrated in vacuo. The residue was diluted with ethyl acetate and washed with an aqueous saturated sodium hydrogencarbonate solution, and dried over magnesium sulfate. After evaporation to remove solvent, the residue was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=6:1) to give chloro(4-chlorophenyl)(4-cyanophenyl)methane (12.4 g, yield: 93%) as an oil.

Reference Example 6

(1) To a solution of (3R)-3-(tert-butyloxycarbonylamino)pyrrolidine (10.0 g) and triethylamine (5.43 g) in methylene chloride (100 mL) was added dropwise a solution of benzyloxycarbonyl chloride (7.7 mL) in methylene chloride (20 mL) over a period of 15 minutes under nitrogen gas atmosphere and ice-cooling and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added water (70 mL) and the mixture was extracted with chloroform. The extract was washed successively with water (70 mL), 5% citric acid solution (70 mL) and a saturated brine (70 mL) and the organic layer was dried over anhydrous magnesium sulfate. After concentration in vacuo, the resultant product was triturated in diisopropylether to give (3R)-1-benzyloxycarbonyl-3-(tert-butoxycarbonylamino)pyrrolidine (11.8 g, yield: 70%) as crystals.

MS(APCI) m/z; 321 [M+H]⁺

(2) To a solution of the compound obtained in the above step (1) (12.1 g) in 1,4-dioxane (100 mL) was added 4N HCl-dioxane (50 mL) and the mixture was stirred at room temperature for 19 hours. The reaction mixture was concentrated in vacuo and the resultant crude product was triturated in diisopropylether to give (3R)-3-amino-1-benzyloxycarbonylpyrrolidine hydrochloride (9.2 g, yield: 94%) as crystals.

MS(APCI) m/z; 283 [M+H]⁺

(3) To a suspension of the compound obtained in the above step (2) (8.23 g), 4-(trifluoromethyloxy)benzoic acid (6.61 g), triethylamine (6.7 mL) and 1-hydroxybenzotriazole (6.83 g) in methylene chloride (82.3 mL) was added 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (7.40 g) and the mixture was stirred at room temperature overnight. To the reaction mixture was added water (58 mL) and the mixture was stirred for 10 minutes. The chloroform layer was separated and washed successively with an aqueous saturated sodium hydrogencarbonate solution (58 mL) and a saturated brine (58 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant crude product was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=2:1→1:1) to give (3R)-1-benzyloxycarbonyl-3-[[4-(trifluoromethoxy)benzoyl]amino]pyrrolidine (11.29 g, yield: 87%) as an oil.

MS(APCI) m/z; 409 [M+H]⁺

(4) To a solution of the compound obtained in the above step (3) (11.29 g) in methanol (114 mL) was added 10% palladium-carbon (0.32 g) and the mixture was stirred at room temperature under atmospheric pressure of hydrogen gas for 1.5 hours. After removal of the insoluble materials by filtration, the filtrate was evaporated in vacuo to give (3R)-3-[[4-(trifluoromethoxy)benzoyl]amino]pyrrolidine (7.76 g, yield: 87%) as an oil.

MS(APCI) m/z; 275 [M+H]⁺

Reference Example 7

(1) To a solution of (3,4-trans)-4-amino-3-ethoxycarbonyl-1-(tert-butoxycarbonyl)pyrrolidine (1.04 g) in methylene chloride (20 mL) was added triethylamine (0.67 mL) and thereto was added dropwise 4-(trifluoromethoxy)benzoyl chloride under ice-cooling. The mixture was stirred at room temperature for 24 hours. To the reaction mixture was added chloroform and the mixture was washed with an aqueous saturated citric acid solution and an aqueous saturated sodium hydrogencarbonate solution and dried over magnesium sulfate. The organic layer was concentrated in vacuo and the crude product was purified by a column chromatography on silica gel (solvent; chloroform/ethyl acetate=10:1) to give (3,4-trans)-3-ethoxycarbonyl-1-(tert-butoxycarbonyl)-4-[[4-(trifluoromethoxy)benzoyl]amino]pyrrolidine (1.34 g, yield: 75%) as an oil.

MS(APCI) m/z; 447 [M+H]⁺

(2) To a solution of the compound obtained in the above step (1) (1.34 g) in chloroform (15 mL) was added 4N HCl-ethyl acetate (5 mL) and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo and the residue was neutralized with 1N sodium hydroxide solution. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The resultant crude product was purified by a column chromatography on silica gel (solvent; chloroform/methanol=49:1) to give (3,4-trans)-3-ethoxycarbonyl-4-[[4-(trifluoromethoxy)benzoyl]amino]-pyrrolidine (943 mg, yield: 91%) as an oil.

MS(APCI) m/z; 347 [M+H]⁺

Reference Example 8

(1) To a solution of 1-benzyloxycarbonyl-3-pyrroline (5.0 g) in methylene chloride (125 mL) was added 3-chloroperbenzoic acid (12.17 g) and the mixture was stirred at room temperature for 3 days. To the reaction mixture was added a saturated sodium thiosulfate solution (100 mL) and the mixture was stirred for 30 minutes. The reaction mixture was extracted with chloroform (×2) and the extract was washed successively with 2N sodium hydroxide solution (100 mL×2) and a saturated brine. The organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo to give benzyl 6-oxa-3-azabicyclo[3,1,0]hexan-3-carboxylate (5.58 g, yield: 100%) as an oil.

MS(APCI) m/z; 220 [M+H]⁺

(2) A mixture of the compound obtained in the above step (1) (5.58 g) and aqueous 28% ammonia was stirred at 40° C. for 2 days. Thereto was added 2N sodium hydroxide solution (50 mL) and the mixture was extracted with chloroform (×3). The organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo to give (3,4-trans)-4-amino-1-benzyloxycarbonyl-3-hydroxy-pyrrolidine (5.34 g, yield: 92%) as an oil.

MS(APCI) m/z; 237 [M+H]⁺

(3) To a solution of the compound obtained in the above step (2) (5.34 g) in chloroform (50 mL) was added dropwise a solution of di-tert-butyl dicarbonate (7.40 g) in chloroform (10 mL) under ice-cooling and the mixture was stirred at room temperature for 19 hours. The reaction mixture was washed with water and the organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo. The resultant crude product was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=2:1→1:1) to give (3,4-trans)-1-benzyloxy-carbonyl-3-hydroxy-4-(tert-butoxycarbonylamino)pyrrolidine (5.55 g, yield: 73%) as crystals.

MS(APCI) m/z; 337 [M+H]⁺

(4) To a solution of the compound obtained in the above step (3) (3.54 g) in methanol (31 mL) and tetrahydrofuran (7 mL) was added palladium hydroxide (20 wt % Pd on carbon, 500 mg) and the mixture was stirred at room temperature under hydrogen gas atmosphere (40 to 45 Parr) overnight. After removal of the insoluble materials by filtration through Cerite, the filtrate was concentrated in vacuo. The residue was triturated in ethyl acetate/diisopropylether to give (3,4-trans)-3-hydroxy-4-(tert-butoxy-carbonylamino)pyrrolidine (2.0 g, yield: 94%) as a powder.

MS(APCI) m/z; 203 [M+H]⁺

Reference Example 9

(1) A mixture of the compound obtained in Reference Example 8-(1) (26.5 g), (1R,2R)-(−)-N,N′-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminochromium (1.57 g) and trimethylsilylazide (17.7 mL) was stirred at room temperature under nitrogen gas atmosphere for 2 days. After addition of chloroform, the reaction mixture was washed successively with water and a saturated brine. The organic later was dried over anhydrous magnesium sulfate and evaporated in vacuo. The resultant crude product was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=10:1→2:1 and then chloroform/methanol=20:1→9:1) to give (3S,4S)-4-azido-1-benzyloxycarbonyl-3-trimethylsilyloxypyrrolidine (Compound a: 20.6 g, yield: 55%) and (3S,4S)-4-azido-1-benzyloxycarbonyl-3-hydroxypyrrolidine (Compound b: 8.16 g, yield: 28%) as an oil, respectively.

Compound a: MS(APCI) m/z; 335 [M+H]⁺

Compound b: MS(APCI) m/z; 263 [M+H]⁺

(2) To a solution of the Compound a (20.6 g) or b (8.16 g) obtained in the above step (1) in tetrahydrofuran (740 mL) was added triphenylphosphine (26.67 g) and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and to the residue was added methanol (380 mL) and 0.5N sodium hydroxide solution (380 mL). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the resultant residue was acidified (pH 3) with 6N HCl and washed with chloroform. The aqueous layer was basified (pH 9) with 5N sodium hydroxide, and the mixture was extracted with chloroform (×3). The organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo to give (3S,4S)-4-amino-1-benzyloxycarbonyl-3-hydroxy-pyrrolidine (19.6 g, yield: 90%) as an oil.

MS(APCI) m/z; 237 [M+H]⁺

(3) The compound obtained in the above step (2) (14.61 g) was treated in the same manner as described in Reference Example 8-(3) to give (3S,4S)-1-benzyl-oxycarbonyl-3-hydroxy-4-(tert-butoxycarbonylamino)pyrrolidine (18.59 g, yield: 94%) as crystals.

MS(APCI) m/z; 337 [M+H]⁺

(4) To a solution of the compound obtained in the above step (3) (18.56 g) in methanol (200 mL) was added 10% palladium-carbon (1.16 g) and the mixture was stirred at room temperature under atmospheric pressure of hydrogen for 3 hours. After removal of the insoluble materials by filtration through Cerite, the filtrate was concentrated in vacuo and then triturated in methanol/diisopropylether to give (3S,4S)-3-hydroxy-4-(tert-butoxycarbonylamino)pyrrolidine (10.8 g, yield: 97%) as crystals.

MS(APCI) m/z; 203 [M+H]⁺

Reference Example 10

(1) To a solution of (2S,4R)-2-carboxy-4-[(9-fluorenyl)methoxycarbonyl-amino]-1-tert-butoxycarbonylpyrrolidine (122 mg) in dichloromethane was added dimethylaminopyridine (6 mg). Thereto was added dropwise a solution of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (120 mg) in dichloromethane and methanol (0.5 mL) under ice-cooling and the mixture was stirred at the same temperature for 2 hours. After addition of water, the organic layer was extracted by diatomaceous earth column (Chem Elut; VARIAN Inc.). The extract was concentrated in vacuo to give crude (2S,4R)-4-[(9-fluorenyl)methoxycarbonylamino]-2-methoxycarbonyl-1-tert-butoxy-carbonylpyrrolidine. To the crude product was added 20% piperidine/dichloromethane solution (5 mL) and the mixture was stirred at room temperature for 1 hour. After evaporation in vacuo, the residue was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=1:1) to give (2S,4R)-4-amino-2-methoxy-carbonyl-1-tert-butoxycarbonyl-pyrrolidine (38 mg, yield: 38%) as an oil.

MS(APCI) m/z; 245 [M+H]⁺

(2) A solution of the compound obtained in the above step (1) (36 mg), 4-chlorobenzoic acid (30 mg), N-hydroxybenzotriazole (30 mg) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (43 mg) in dimethylformamide (0.5 mL) was stirred at room temperature for 15 hours. To the reaction mixture was added a saturated brine and the aqueous layer was extracted with ethyl acetate (×2). The organic layer was concentrated in vacuo and the residue was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=1:1) to give (2S,4R)-4-[(4-chlorobenzoyl)-amino]-2-methoxycarbonyl-1-tert-butoxycarbonylpyrrolidine (37 mg, yield: 64%) as an oil.

MS(ESI) m/z; 383, 385 [M+H]⁺

(3) A mixture of the compound obtained in the above step (37 mg) and 4N HCl-dioxane (5 mL) was stirred at room temperature for 15 hours and the reaction mixture was concentrated in vacuo to give (2S,4R)-4-[(4-chlorobenzoyl)amino]-2-methoxycarbonylpyrrolidine.

Reference Example 11

(1) Bis-(4-chlorophenyl)methanol (100 g) was treated in the same manner as described in Reference Example 5-(2) to give chloro[bis(4-chlorophenyl)]methane (100.5 g, yield: 94%).

MS(EI) m/z; 270 [M+]⁺

(2) The compound obtained in the above step (1) (14.5 g) and (3R)-tert-butyloxycarbonylaminopyrrolidine (10 g) were treated in the same manner as described in Example 5 to give (3R)-1-[bis-(4-chlorophenyl)methyl]-3-tert-butoxy carbonylaminopyrrolidine (18.8 g, yield: 83%) as an oil.

MS(APCI) m/z; 421 [M+H]⁺

(3) A mixture of the compound obtained in the above step (2) (18 g), trifluoroacetic acid (30 mL) and methylene chloride was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo and to the residue was added an aqueous HCl solution to dissolve precipitates. The solution was washed with diethylether. The aqueous layer was basified with potassium carbonate and extracted with ethyl acetate. The organic layer was washed with water and a saturated brine, dried over sodium sulfate and evaporated in vacuo to give (3R)-3-amino-1-[bis-(4-chlorophenyl)-methyl]pyrrolidine as an oil.

MS(APCI) m/z; 321, 323 [M+H]⁺

Reference Example 12

The corresponding materials (4-oxo-3-ethoxycarbonyl-1-tert-butoxycarbonyl-pyrrolidine) were treated in the same manner as described in WO03/025577 (page 27) to give (3S,4S)-4-amino-3-ethoxycarbonyl-1-tert-butoxycarbonylpyrrolidine.

Reference Example 13

(1) The compound obtained in Reference Example 12 (1.04 g) and 4-cyano-benzoyl chloride (662 mg) were treated in the same manner as described in Reference Example 7-(1) to give (3S,4R)-1-(tert-butoxycarbonyl)-3-ethoxycarbonyl-4-[(4-cyano-benzoyl)amino]pyrrolidine (624 mg, yield: 40%) as an oil.

MS(APCI) m/z; 388 [M+H]⁺

(2) The compound obtained in the above step (1) (624 mg) was treated in the same manner as described in Reference Example 7-(2) to give (3S,4R)-3-ethoxy-carbonyl-4-[(4-cyanobenzoyl)amino]pyrrolidine (94 mg, yield: 20%).

MS(APCI) m/z; 288 [M+H]⁺

Reference Example 14

(1) The compound obtained in Reference Example 12 (2.07 g) and 4-(trifluoromethoxy)benzoyl chloride (1.51 mL) were treated in the same manner as described in Reference Example 7 to give (3S,4R)-1-(tert-butoxycarbonyl)-3-ethoxy-carbonyl-4-[[4-(trifluoromethoxy)benzoyl]amino]pyrrolidine (3.3 g, yield: 92%).

MS(APCI) m/z; 447 [M+H]⁺

(2) The compound obtained in the above step (1) (3.3 g) was treated in the same manner as described in Example 514-(2) and (3) to give (3S,4R)-1-(tert-butoxy-carbonyl)-3-ethoxymethyl-4-[[4-(trifluoromethoxy)benzoyl]amino]pyrrolidine (1.14 g, yield: 35%).

MS(APCI) m/z; 433 [M+H]⁺

(3) The compound obtained in the above step (2) (1.14 g) was treated in the same manner as described in Reference Example 7-(2) to give (3S,4R)-3-ethoxy-methyl-4-[[4-(trifluoromethoxy)benzoyl]amino]pyrrolidine (832.5 mg, yield: 95%).

Reference Example 15

(1) The compound obtained in Reference Example 5 (48.8 g) and (3R)-3-(tert-butoxycarbonylamino)pyrrolidine (28.87 g) were treated in the same manner as described in Example 6 to give (3R)-1-[(4-cyanophenyl)(4-chlorophenyl)-methyl]-3-(tert-butoxycarbonylamino)pyrrolidine (a mixture of diastereomers, 58.1 g, yield: 90.1%).

(2) The mixture obtained in the above step (1) was resolved by a chiral column (CHIRALPACK AD-H; DAICEL CHEMICAL) to give optically active (3R)-1-[(S)-(4-cyanophenyl)(4-chlorophenyl)methyl]-3-(tert-butoxycarbonylamino)-pyrrolidine (22.2 g, yield: 38.2%) and (3R)-1-[(R)-(4-cyanophenyl)(4-chlorophenyl)-methyl]-3-(tert-butoxycarbonylamino)pyrrolidine (22.4 g, yield: 38.6%).

Reference Example 16

(1) To a solution of sodium hydride (0.5 g) in dimethylformamide (15 mL) was added a solution of the compound obtained in Reference Example 9-(1) (compound b, 2.21 g) in dimethylformamide (10 mL) under ice-cooling and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 2-methoxyethyl bromide (1.59 mL) and the mixture was stirred at room temperature overnight. After ice-cooling, to the reaction mixture was added sodium hydride (0.5 g) and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was further added 2-methoxyethyl bromide (1.59 mL) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with diethylether and thereto was added water. The mixture was extracted with ethyl acetate (×2) and the organic layer was concentrated in vacuo. The residue was purified by a column chromatography on silica gel (Solvent; hexane/ethyl acetate=85:15→65:35) to give (3S,4S)-4-azido-1-benzyloxy-carbonyl-3-[2-(methoxy)ethoxy]pyrrolidine (1.78 g, yield: 66%) as an oil. MS(APCI) m/z; 321 [M+H]⁺

(2) The compound obtained in the above step (1) (2.03 g) was treated in the same manner as described in Reference Example 9-(2) to give (3S,4S)-4-amino-1-benzyloxycarbonyl-3-[2-(methoxy)ethoxy]pyrrolidine (1.82 g, yield: 98%) as an oil. MS(APCI) m/z; 295 [M+H]⁺

(3) The compound obtained in the above step (2) (1.82 g) was treated in the same manner as described in Reference Example 8-(3) to give (3S,4S)-1-benzyloxy-carbonyl-3-[2-(methoxy)ethoxy]-4-(tert-butoxycarbonylamino)pyrrolidine (2.25 g, yield: 92%) as an oil. MS(APCI) m/z; 395 [M+H]⁺

(4) To a solution of the compound obtained in the above step (3) (2.25 g) in methanol (40 mL) was added 10% palladium-carbon (200 mg) and the mixture was stirred at room temperature under atmospheric pressure of hydrogen gas for 4 hours. The precipitates were removed by filtration through Cerite and the filtrate was concentrated in vacuo to give (3S,4S)-3-[2-(methoxy)ethoxy]-4-(tert-butoxycarbonyl-amino)pyrrolidine (1.46 g, yield: 98%) as an oil.

MS(APCI) m/z; 261 [M+H]⁺

Reference Example 17

(1) To 4-bromobenzaldehyde (555 mg) was added [bis(2-methoxyethyl)amino]sulfur trifluoride (555 μL) under ice-cooling and the mixture was stirred at room temperature (under ice cooling, if required) for 30 minutes and then stirred at 60° C. for 2 hours. The resultant crude product was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=100:0→95:5) to give 1-bromo-4-(difluoromethyl)-benzene (328 mg, yield: 53%).

G-CMS(EI) m/z: 208/210

(2) To a solution of the compound obtained in the above step (1) (310 mg) in tetrahydrofuran (3 mL) was added dropwise 1.58M n-butyl lithium/hexane (2.37 mL) at −78° C. under nitrogen gas atmosphere and the mixture was stirred at the same temperature 1 hour. To the reaction mixture was added dropwise a solution of 4-cyanobenzaldehyde (197 mg) in tetrahydrofuran (2 mL) and the mixture was stirred at the same temperature for 3 hours. The reaction mixture was concentrated in vacuo and to the residue was added water and ethyl acetate. After stirring, the mixture was extracted with ethyl acetate and the organic layer was filtered through NH-silica gel (Chromatorex NH-silica gel, 2 g). The filtrate was concentrated in vacuo and the crude product was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=80:20→65:35) to give (4-cyanophenyl)[4-(difluoromethyl)phenyl]methanol (83.2 mg, yield: 21%).

(3) To the compound obtained in the above step (2) (38.9 mg) was added thionyl chloride (2 mL) and the mixture was stirred at 85° C. for 2 hours. The reaction mixture was concentrated to give chloro(4-cyanophenyl)[4-(difluoromethyl)phenyl]methane.

Reference Example 18

(1) To a solution of 6-methylnicotinic acid (1 g) in tetrahydrofuran (10 mL) was added lithium aluminum hydride (277 mg) and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added an aqueous solution of sodium hydroxide and water. After stirring, the mixture was filtered and the organic layer was separated and concentrated in vacuo. The resultant crude product was purified by a column chromatography on silica gel (solvent; chloroform/methanol=98:2→90:10) to give 6-methylpyridin-3-ylmethyl alcohol (434 mg, yield: 49%).

MS(APCI) m/z: 124 [M+H]⁺

(2) To a solution of the compound obtained in the above step (1) (430 mg) in methylene chloride (10 mL) was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (1.48 g) and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added an aqueous saturated sodium hydrogencarbonate solution. After stirring, the mixture was extracted with chloroform and the extract was concentrated in vacuo. The resultant crude product was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=70:30→50:50) to give 6-methylpyridin-3-carbaldehyde (224 mg, yield: 53%).

MS(APCI) m/z: 122 [M+H]⁺

(3) To a solution of 4-iodobenzonitrile (460 mg) in tetrahydrofuran (5 mL) was added dropwise 1.58M n-butyl lithium/hexane (1.25 mL) at −78° C. under nitrogen gas atmosphere and the mixture was stirred at the same temperature for 30 minutes. Thereto was added the compound obtained in the above step (2) (220 mg) and the mixture was stirred at the same temperature for 1 hour. After warming to room temperature, to the reaction mixture was added water and ethyl acetate. After stirring, the organic layer was separated and concentrated in vacuo. The resultant crude product was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=50:50→0:100) to give (4-cyanophenyl)(6-methylpyridin-3-yl)methanol (111 mg, yield: 27%).

MS(APCI) m/z: 225 [M+H]⁺

Reference Example 19

(1) A mixture of 4-dimethylsulfamoylbenzoic acid (688 mg) and thionyl chloride (5 mL) was stirred at 90° C. overnight. The reaction mixture was concentrated to give 4-dimethylsulfamoylbenzoyl chloride (495 mg) as a white solid.

(2) To a solution of 4-cyanophenylboronic acid (353 mg), [bis-(triphenyl-phosphino)-dichloro]palladium (28 mg) and potassium phosphate trihydrate (692 mg) in toluene (5 mL) was added the compound obtained in the above step (1) (495 mg) and the mixture was stirred at 110° C. for 1.5 hours. After cooling to room temperature, the reaction mixture was filtered through silica gel (5 g) and the filtrate was concentrated in vacuo. The resultant crude product was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=33:67→65:35) to give (4-cyanophenyl)(4-dimethylsulfamoylphenyl)ketone (234 mg) as a white solid.

(3) To a solution of the compound obtained in the above step (2) (234 mg) in tetrahydrofuran (5 mL) and methanol (1 mL) was added sodium borohydride (56 mg) at 0° C. and the mixture was stirred at the same temperature for 10 minutes and then stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and thereto was added water and ethyl acetate. After stirring, the organic layer was extracted by a diatomaceous earth column (Chem Elut). The extract was concentrated in vacuo and the resultant crude product was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=70:30→50:50) to give (4-cyanophenyl)(4-dimethyl-sulfamoylphenyl)methanol as a viscous liquid.

Reference Example 20

(1) To a solution of 5-bromo-1H-pyridin-2-one (2 g) and silver carbonate (4.3 g) in chloroform (40 mL) was added isopropyl iodide (11.5 mL) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through silica gel (20 g) and the filtrate was concentrated in vacuo. The resultant crude product was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=98:2→90:10) to give 5-bromo-2-isopropyloxypyridine (2.41 g, yield: 97%).

MS(APCI) m/z: 216/218 [M+H]⁺

(2) The compound obtained in the above step (1) (2.4 g) was treated in the same manner as described in Reference Example 17(2) to give (4-cyanophenyl)(6-isopropyl-oxypyridin-3-yl)methanol (1.88 g; yield: 63%).

MS(APCI) m/z: 269 [M+H]⁺

Reference Example 21

(1) The corresponding starting materials were treated in the same manner as described in Reference Example 1(2) to give (4-cyanophenyl)(4-methoxycarbonyl-phenyl)methanol. Subsequently, the product was reacted with phosphorus tribromide to give bromo(4-cyanophenyl)(4-methoxycarbonylphenyl)methane.

MS(APCI) m/z: 259/261 [M+H]⁺

(2) The compound obtained in the above step (1) and the compound obtained in Reference Example 6 were treated in the same manner as described in Example 6 to give (3R)-1-[(4-cyanophenyl)(4-methoxycarbonylphenyl)methyl]-3-[[4-(trifluoromethyl)-benzoyl]amino]pyrrolidine (427 mg).

MS(APCI) m/z: 533/535 [M+H]⁺

(3) The compound obtained in the above step (2) was treated in the same manner as described in Example 19(1) to give (3R)-1-[(4-carboxyphenyl)(4-cyanophenyl)-methyl]-3-[[4-(trifluoromethyl)benzoyl]amino]pyrrolidine (344 mg).

MS(APCI) m/z: 519/521 [M+H]⁺

Reference Example 22

(1) To a solution of 5-methyl-2-pyrazinecarboxylic acid (1.0 g) in tetrahydrofuran (10 mL) was added triethylamine (1.1 mL) and isobutyl chloroformate (1.0 mL), and the mixture was stirred at 0° C. for 30 minutes. To the reaction mixture was added sodium borohydride (603 mg) and methanol (5 mL) at −78° C. After stirring, to the mixture was added aqueous ammonium chloride and the mixture was extracted with ethyl acetate. The organic layer was separated and concentrated in vacuo. The resultant crude product was purified by a column chromatography on silica gel (solvent; chloroform/methanol=90:10) to give 5-methylpyrazin-2-ylmethyl alcohol (592 mg, yield: 66%).

MS(APCI) m/z: 125 [M+H]⁺

(2) The compound obtained in the above step (1) was treated in the same manner as described in Reference Example 18(2) and (3) to give (4-cyanophenyl)(5-methyl-pyrazin-2-yl)methanol (44 mg, yield: 8.1%).

MS(APCI) m/z: 226 [M+H]⁺

Reference Example 23

(1) To a solution of sodium isopropyloxide (984 mg) in isopropanol (10 mL) was added 2-chloro-5-bromopyrimidine (1.934 g) and the mixture was stirred at room temperature for 2 hours under nitrogen gas atmosphere. To the reaction mixture was added water and ethyl acetate. After stirring, the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resultant crude product was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=100:0→90:10) to give 2-isopropyl-oxy-5-bromopyrimidine (1.7 g, yield: 78%).

MS(APCI) m/z: 217/219 [M+H]⁺

(2) To a solution of the compound obtained in the above step (1) (434 mg) in tetrahydrofuran (20 mL) and diethylether (20 mL) was added dropwise 1.58 M butyl lithium (1.27 mL) at a temperature below −100° C. over a period of 5 minutes and the mixture was stirred at the same temperature for 30 minutes. Thereto was added dropwise 4-cyanobenzaldehyde (262 mg) in tetrahydrofuran (5 mL) at the same temperature for 3 hours. After warming to room temperature, to the reaction mixture was added water and ethyl acetate. After stirring, the mixture was extracted with ethyl acetate. The extracts was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and the resultant crude product was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=60:40→30:70) to give (4-cyanophenyl)(2-isopropyloxy-pyrimidin-5-yl)methanol (174 mg, yield: 32%).

MS(APCI) m/z: 270 [M+H]⁺

Reference Example 24

(1) To a solution of 4-bromobenzylalcohol (561 mg) in methylene chloride (3 mL) was added [bis-(2-methoxyethyl)amino]sulfur trifluoride (590 μL) over a period of 5 minutes under ice-cooling and the mixture was stirred at the same temperature for 1 hours and then stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and the resultant crude product was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=100:0→95:5) to give 1-bromo-4-fluoromethyl-benzene (340 mg, yield: 60%).

GCMS(EI) m/z: 188/190

(2) The compound obtained in the above step (1) (300 mg) was treated in the same manner as described in Reference Example 17(2) to give (4-cyanophenyl)(4-fluoro-methylphenyl)methanol (227 mg, yield: 59%).

Reference Example 25

(1) To a solution of 5-bromo-2-methylpyridine (5.0 g) in carbon tetrachloride (50 mL) was added N-bromosuccinimide (6.2 g) and 2,2′-azobis(2-methylpropionitrile) (239 mg) and the mixture was stirred at 85° C. for 1 hour. After cooling, the reaction mixture was filtered to remove the insoluble materials and the filtrate was concentrated in vacuo. The resultant crude product was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=100:0→92:8) to give 5-bromo-2-bromomethyl-pyridine (3.7 g, yield: 51%).

MS(APCI) m/z: 250/252 [M+H]⁺

(2) To a solution of sodium isopropyloxide (1.82 g) in isopropanol (24 mL) was added the compound obtained in the above step (1) (1.85 g) in 2-propanol (10 mL) at 85° C. and the mixture was stirred for 30 minutes. After cooling, the reaction mixture was concentrated in vacuo and thereto was added water and ethyl acetate. The mixture was extracted with chloroform and the extract was concentrated in vacuo. The resultant crude product was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=99:1→90:10) to give 5-bromo-2-isopropyloxymethyl-pyridine (1.47 g, yield: 87%).

MS(APCI) m/z: 230/232 [M+H]⁺

(3) The compound obtained in the above step (2) (400 mg) and 4-trifluoro-methylbenzaldehyde were treated in the same manner as described in Reference Example 17(2) to give (6-isopropyloxymethylpyridin-3-yl)(4-trifluoromethylphenyl)methanol (333 mg, yield: 57%).

MS(APCI) m/z: 326 [M+H]⁺

Reference Example 26

(1) To a solution of sodium isopropyloxide (10.0 g) in 2-propanol (100 mL) was added 2-bromothiazol (10.0 g) at 85° C. and the mixture was stirred for 15 hours. After cooling, the reaction mixture was concentrated in vacuo and thereto was added water. The mixture was extracted with diethylether and the extract was washed with water and a saturated brine, dried over magnesium sulfate and concentrated in vacuo to give 2-isopropyloxythiazol (6.39 g, yield: 73%). MS(APCI) m/z: 144 [M+H]⁺

(2) The compound obtained in the above step (1) (1.0 g) was treated in the same manner as described in Reference Example 17(2) to give (4-cyanophenyl)(2-isopropyloxythiazol-5-yl)methanol (1.62 g, yield: 85%).

MS(APCI) m/z: 275 [M+H]⁺

Reference Example 27

To a solution of 2,2,2-trifluoroethanol (3.1 g) in dioxane (20 mL) was added sodium hydride (1.4 g) at 0° C. and the mixture was stirred at room temperature under nitrogen gas atmosphere for 30 minutes. Thereto was added 5-bromo-2-chloro-pyrimidine (3.0 g) and the mixture was stirred at room temperature overnight. Thereto was added water and ethyl acetate and the mixture was stirred and filtered. The filtrate was concentrated in vacuo and the resultant crude product was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=95:5→90:10) to give 5-bromo-2-(2,2-trifluoroethoxy)-pyrimidine (3.0 g, yield: 38%).

MS(APCI) m/z; 257/259 [M+H]⁺

Reference Example 28

(1) To a solution of the compound obtained in Reference Example 20-(1) (1.0 g) in tetrahydrofuran (10 mL) was added dropwise 1.58 M n-butyl lithium (3.0 mL) at −78° C. under nitrogen gas atmosphere and the mixture was stirred at the same temperature for 1 hours. Thereto was added a solution of 6-chloro-3-formylpyridine (660 mg) in tetrahydrofuran (2 mL) and the mixture was stirred at the same temperature for 1 hour. After warming to room temperature, thereto was added water and the mixture was extracted with ethyl acetate. The extract was concentrated in vacuo and the resultant crude product was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=80:20→60:40) to give (6-chloropyridin-3-yl)(6-isopropyloxy-pyridin-3-yl)methanol (733 mg, yield: 57%).

MS(APCI) m/z; 279/281 [M+H]⁺

(2) To a solution of the compound obtained in the above step (1) (733 mg) and triethylamine (735 μL) in methylene chloride (12 mL) was added dropwise methanesulfonyl chloride (245 μL) under ice cooling and the mixture was stirred at the same temperature for 1 hour. Thereto was added (3R)-(+)-(tert-butoxycarbonylamino)pyrrolidine (637 mg) and acetonitrile (25 mL) and the mixture was stirred at 85° C. for 18 hours. Thereto was added water and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo. The resultant crude product was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=90:10→67:33) to give (3R)-1-[(6-chloro-pyridin-3-yl)(6-isopropyloxypyridin-3-yl)methyl]-3-(tert-butoxycarbonylamino)-pyrrolidine (635 mg, yield: 54%).

MS(APCI) m/z; 447/449 [M+H]⁺

(3) To a solution of the compound obtained in the above step (2) (506 mg) in 2-propanol (15 mL) was added sodium isopropoxide (411 mg) and the mixture was stirred by using a microwave synthesizer (Biotage LTD.) at 155° C. for 2 hours. Thereto was added an aqueous saturated sodium hydrogencarbonate solution and the mixture was extracted with chloroform. The extract was dried over magnesium sulfate and concentrated in vacuo to give (3R)-3-amino-1-[(6-chloropyridin-3-yl)(6-isopropyl-oxypyridin-3-yl)methyl]pyrrolidine (476 mg) as a brown oil.

Reference Example 29

To a solution of 4-fluorobenzaldehyde (1.5 g) and methylethylamine (1.56 mL) in dimethylsulfoxide (9 mL) was added potassium carbonate (2.17 g) and the mixture was stirred by using a microwave synthesizer (Biotage LTD.) at 120° C. for 2 hours. Thereto was added water and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated in vacuo. The resultant crude product was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=95:5→80:20) to give 4-(N-ethyl-N-methylamino)benzaldehyde (1.89 g, yield: 89%).

MS(APCI) m/z; 164 [M+H]⁺

Reference Example 30

To a solution of 4-hydroxybenzaldehyde (1.22 g) in pyridine (5 mL) was added dimethylcarbamyl chloride (1.0 mL) and the mixture was stirred at 60° C. overnight. Thereto was added diluted HCl and ethyl acetate and stirred. The organic layer was extracted by diatomaceous earth column. The organic layer was concentrated and the resultant crude product was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=80:20→60:40) to give 4-formylphenyl dimethylcarbamate (1.67 g, yield: 86%).

MS(APCI) m/z; 194 [M+H]⁺

INDUSTRIAL APPLICABILITY

A compound [I] of the present invention may be useful as: (i) an agent for prevention and/or treatment of a CB1 receptor-mediated diseases exemplified as above; (ii) an agent for withdrawal from a chronic treatment, alcohol dependence, smoking dependence, nicotine dependence, or drug abuse (e.g., an opioid, barbiturate, marijuana, cocaine, amphetamine, phencyclidine, a hallucinogenic agent, a benzodiazepine compound and the like); or (iii) an agent for enhancing analgesic activity of analgesic or narcotic drugs and the like. 

1. A compound of the formula [I]:

wherein each of R¹ and R² is (A) independently (a) a phenyl group optionally substituted by the same or different one to two group(s) selected from the group consisting of (i) a halogen atom, (ii) cyano group, (iii) an alkyloxy group optionally substituted by a morpholino group, (iv) an amino group optionally substituted by a group selected from the group consisting of an alkyl group, an alkyloxyalkyl group and a cycloalkyl group, (v) an alkylthio group and (vi) an alkylenedioxy group, (b) a thienyl group optionally substituted by a halogen atom, (c) a quinolyl group, (d) a thiazolyl group optionally substituted by an alkyloxy group, (e) a morpholinyl group, (f) a pyrimidinyl group optionally substituted by a di(alkyl)amino group, (g) a benzimidazolyl group optionally substituted by an alkyl group or (h) a pyridyl group optionally substituted by a group selected from the group consisting of a cycloalkyloxy group or an alkyloxy group optionally substituted by one to three halogen atom(s), or (B) both of the groups combine each other together with an adjacent CH group to form a group of the formula:

either one of R³ and R⁴ is a hydrogen atom and another is a hydrogen atom, a hydroxyl group, a hydroxyalkyl group, an alkyloxy group, an alkyloxyalkyl group, an alkyloxyalkyloxy group, a carboxyl group, an alkyloxycarbonyl group, a saturated or unsaturated, 4- to 10-membered, nitrogen- or oxygen-containing heterocyclic group, a carbamoyl group or a mono- or dialkylcarbamoyl group (the alkyl moiety of said group being optionally substituted by a group selected from a halogen atom, a hydroxyl group, a mono- or di-alkylamino group and a saturated or unsaturated, 4- to 10-membered, nitrogen- or oxygen-containing heterocyclic group) or both of R³ and R⁴ combine each other to form an oxo group, R⁵ is a hydrogen atom or an alkyl group, Y is a single bond, an oxygen atom or a group of the formula: —N—(R⁷)—, R⁶ is: a cyclic group selected from (i.) a monocyclo-, bicyclo or tri-cyclo-C₃₋₁₀ alkyl group (said cycloalkyl group being fused to a benzene ring) and (ii.) a saturated or unsaturated, 3- to 14-membered, sulfur-, nitrogen- or oxygen-containing heterocyclic group optionally forming a spiro-ring with a cycloalkyl ring, wherein said cyclic group may be optionally substituted by the same or different one to four groups selected from (1) a halogen atom, (2) an oxo group, (3) a nitro group, (4) a cyano group, (5) an alkyl group optionally substituted by the same or different one to three groups selected from a halogen atom, a 5- to 10-membered aryl-carbonyl group, a mono-, di- or tri-halogeno-arylcarbonyl group, a 5- to 10-membered aryl group, a hydroxyl group, a saturated or unsaturated, 4- to 10-membered, nitrogen- or oxygen-containing heterocyclic group optionally substituted by an oxo group, an alkyloxy group and an imino group, (6) an aminoalkyl group (the amino moiety of said group being optionally substituted by the same or different one to two groups selected from an alkyloxycarbonyl group, a 5- to 10-membered aryl-carbonyl group, a 5- to 10-membered aryl-alkyloxy-carbonyl group, an alkyl group, an alkyloxyalkyl group and a cycloalkyl group), (7) a cycloalkyl group, (8) an alkenyl group optionally substituted by an alkyloxycarbonyl group, (9) an amino group optionally substituted by one to two groups selected from an alkyl group, an alkyloxycarbonyl group, a 5- to 10-membered aryl-alkyloxycarbonyl group, an alkyloxyalkyl group and a halogenoalkylcarbonyl group, (10) a 5- to 10-membered aryl group optionally substituted by the same or different one to three groups selected from a halogen atom and a saturated or unsaturated, 4- to 10-membered, nitrogen- or oxygen-containing heterocyclic group, (11) a saturated or unsaturated, 4- to 10-membered, nitrogen- or oxygen-containing heterocyclic group optionally substituted by the same or different one to three groups selected from a halogen atom, an oxo group and a saturated or unsaturated, 4- to 10-membered, nitrogen- or oxygen-containing heterocyclic group, (12) an alkyloxy group optionally substituted by the same or different one to three groups selected from a halogen atom, an alkyloxy group, a 5- to 10-membered aryl group, a saturated or unsaturated, 4- to 10-membered, nitrogen- or oxygen-containing heterocyclic group and a mono- or di-alkylamino group, (13) a cycloalkyloxy group, (14) a cycloalkenyloxy group, (15) a 5- to 10-membered aryl-oxy group, (16) a 5- to 10-membered aryl-carbonyl group optionally substituted by the same or different one to three halogen atoms, (17) an alkylcarbonyl group, (18) an alkyloxycarbonyl group, (19) a 5- to 10-membered aryl-alkyloxycarbonyl group, (20) a group of the formula: —SO₂R_(b) in which R_(b) is an alkyl group, an aryl group optionally substituted by one to three halogen atoms, an amino group optionally substituted by one to two alkyl groups or a saturated or unsaturated, 4- to 10-membered, nitrogen- or oxygen-containing heterocyclic group optionally substituted by the same or different one to three alkyl groups, (21) an alkynyl group optionally substituted by a group selected from a mono- or di-alkylamino group and a saturated or unsaturated, 4- to 10-membered, nitrogen- or oxygen-containing heterocyclic group, (22) an alkylthio group (the alkyl moiety of said group being optionally substituted by a group selected from a hydroxyl group and an alkyloxy group), (23) a carbamoyl group (the amino moiety of said group being optionally substituted by an alkyl group) and (24) a carbamoyloxy group optionally substituted by one or two alkyl groups; and R⁷ is an alkyl group or an alkyloxycarbonyl-alkyl group, or a pharmaceutically acceptable salt thereof.
 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof in which R¹ and R² are the same or different and a phenyl group optionally substituted by one or two halogen atoms, either one of R³ and R⁴ is a hydrogen atom, another is a hydrogen atom or a C₁₋₆ alkyloxy group, R⁵ is a hydrogen atom, Y is a single bond and R⁶ is a C₃₋₁₀ mono- bi- or tri-cycloalkyl group (said cycloalkyl group being optionally fused to a benzene ring) optionally substituted by one to four groups selected from the group consisting of the following (i) to (vi): (i) an oxo group; (ii) a C₁₋₆ alkyl group optionally substituted by a halogenophenyl-carbonyl group; (iii) an amino-a C₁₋₆ alkyl group (amino moiety of said group being optionally substituted by a C₁₋₆ alkyloxy-carbonyl group; (iv) an amino group optionally substituted by a C₁₋₆ alkyloxy-carbonyl group; (v) a phenyl group optionally substituted by one to three halogen atoms; and (vi) a benzoyl group optionally substituted by one to three halogen atoms.
 3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof in which R¹ and R² are the same or different and a (a) phenyl group optionally substituted by one to three groups selected from a halogen atom, a cyano group, a C₁₋₆ alkyloxy group, a trifluoro-C₁₋₆ alkyl group, an amino group substituted by one or two groups selected from a C₁₋₆ alkyl group and a C₁₋₆ alkyloxy-C₁₋₆ alkyl group and a di(C₁₋₆ alkyl)carbamoyloxy group, or (b) a sulfur-, oxygen- or nitrogen-containing 5- to 10-membered heterocyclic group optionally substituted by one to three groups selected from a C₁₋₆ alkyloxy group, a di(C₁₋₆ alkyl)amino group, a C₃₋₈ cycloalkyloxy group, a C₃₋₈ cycloalkyl-C₁₋₆ alkyloxy group and a trihalogeno-C₁₋₆ alkyloxy group, one of R³ and R⁴ is a hydrogen atom, another is a hydrogen atom or a C₁₋₆ alkyloxy group, R⁵ is a hydrogen atom, Y is a single bond and R⁶ is a saturated or unsaturated 3- to 14-membered, monocyclic- bicyclic- or tricyclic-heterocyclic group (said heterocyclic group optionally constituting a spiro-ring with a C₃₋₈ cycloalkyl group) optionally substituted by one to three groups selected from the group consisting of the following (i) to (xiv): (i) an oxo group; (ii) a halogen atom; (iii) a cyano group; (iv) a C₁₋₆ alkyl group (said group being optionally substituted by one to three groups selected from a halogen atom, a C₁₋₆ alkyloxy group, an imino group, a phenyl group and a pyrrolidinyl group); (v) an amino-C₁₋₆ alkyl group (amino moiety of said group being optionally substituted by one or two C₁₋₆ alkyl groups); (vi) an amino group optionally substituted by one or two C₁₋₆ alkyl groups; (vii) a phenyl group optionally substituted by one to three halogen atoms; (viii) a heterocyclic group selected from a furyl group, a pyridyl group and a pyrimidinyl group; (ix) a C₁₋₆ alkyloxy group optionally substituted by one to three groups selected from halogen atoms and a phenyl group; (x) a C₁₋₆ alkyl-carbonyl group; (xi) a C₁₋₆ alkyloxy-carbonyl group; (xii) a C₁₋₆ alkylsulfonyl group; (xiii) an aminosulfonyl group; (xiv) a benzenesulfonyl group optionally substituted by one to three halogen atoms; and (xv) a morpholinosulfonyl group.
 4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof in which R⁶ is a mono-, bi- or tri- cycloalkyl group (said cycloalkyl group being optionally fused by a benzene ring) substituted by the same or different one to four groups selected from an oxo group, a C₁₋₆ alkyl group, a halogenobenzoyl-C₁₋₆ alkyl group, a C₁₋₆ alkyloxy-carbonylamino group, a C₁₋₆ alkyloxy-carbonylamino-C₁₋₆ alkyl group, a halogenobenzoyl group, a phenyl group and a halogenophenyl group.
 5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof in which R⁶ is a heterocyclic group substituted by the same or different one to three groups selected from an oxo group, a chlorine atom, a bromine atom, a cyano group, a C₁₋₆ alkyl group, a C₁₋₆ alkyloxy group, a diphenyl-C₁₋₆ alkyl group, a C₁₋₆ alkyl-carbonyl group, a trifluoro-C₁₋₆ alkyl group, a trifluoro-C₁₋₆ alkyloxy group, a C₁₋₆ alkyloxy-carbonyl group, a di(C₁₋₆ alkylamino-C₁₋₆ alkyl group, a di(C₁₋₆ alkylamino group, a phenyl group, a chlorophenyl group, a pyrrolidinyl-C₁₋₆ alkyl group, a pyridyl group, a pyrimidinyl group, a furyl group, a C₁₋₆ alkylsulfonyl group, an aminosulfonyl group, a morpholinosulfonyl group, a benzene-sulfonyl group, a C₁₋₆ alkyloxy-imino-C₁₋₆ alkyl group, a chlorobenzenesulfonyl group, a benzyl group and a benzyloxy group.
 6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof in which one of R³ and R⁴ is a hydrogen atom and the other is a hydrogen atom, a hydroxyl group, a C₁₋₆ alkyloxy group or a morpholino group.
 7. A compound selected from the group consisting of: (3R)-1-[(4-cyanophenyl)(4-chlorophenyl)methyl]-3-[[5-(trifluoromethyl)-2-thenoyl]amino]pyrrolidine; (3R)-1-[(4-cyanophenyl)(2-isopropyloxythiazol-5-yl)methyl]-3-[(6-cyanonicotinoyl)amino]pyrrolidine, (3R)-1-[(4-methoxyphenyl)(6-isopropyloxypyridin-3-yl)methyl]-3-[[(6-cyanopyridin-3-yl)carbonyl]amino]pyrrolidine; (3R)-1-[(4-ethoxyphenyl)(6-isopropyloxypyridin-3-yl)methyl]-3-[[(6-cyanopyridin-3-yl)carbonyl]amino]pyrrolidine; (3R)-1-[(4-isopropyloxyphenyl)(6-isopropyloxypyridin-3-yl)methyl]-3-[[(6-cyanopyridin-3-yl)carbonyl]amino]pyrrolidine; (3R)-1-[(4-cyanophenyl)(2-ethoxythiazol-5-yl)methyl]-3-[[(6-cyanopyridin-3-yl)carbonyl]amino]pyrrolidine; (3R)-1-[bis-(6-isopropyloxypyridin-3-yl)methyl]-3-[[(6-cyanopyridin-3-yl)carbonyl]amino]pyrrolidine; (3R)-1-[(4-cyanophenyl)(2-dimethylaminopyrimidin-5-yl)methyl]-3-[[(6-cyanopyridin-3-yl)carbonyl]amino]pyrrolidine; (3R)-1-[(4-cyanophenyl)(2-diethylaminopyrimidin-5-yl)methyl]-3-[[(6-cyanopyridin-3-yl)carbonyl]amino]pyrrolidine; (3R)-1-[(4-cyanophenyl)[4-[N-(2-methoxyethyl)-N-methylaminophenyl]]-methyl]-3-[[(6-cyanopyridin-3-yl)carbonyl]amino]pyrrolidine; (3R)-1-[(4-cyanophenyl)[4-[N-(2-methoxyethyl)-N-methylaminophenyl]]methyl]-3-[[(6-cyanopyridin-3-yl)carbonyl]amino]pyrrolidine; (3R)-1-[(4-cyanophenyl)[4-(N-isopropyl-N-methylamino)phenyl]methyl]-3-[[(6-cyanopyridin-3-yl)carbonyl]amino]pyrrolidine; (3R)-1-[(4-cyanophenyl) [4-(N-ethyl-N-methylamino)phenyl]methyl]-3-[[(6-cyanopyridin-3-yl)carbonyl]amino]pyrrolidine; (3R)-1-[(4-cyanophenyl) [4-(N-methyl-N-n-propylamino)phenyl]methyl]-3-[[(6-cyanopyridin-3-yl)carbonyl]amino]pyrrolidine; (3R)-1-[(4-cyanophenyl)(6-cyclobutyloxypyridin-3-yl)methyl]-3-[[(6-cyanopyridin-3-yl)carbonyl]amino]pyrrolidine; (3R)-1-[(4-cyanophenyl)(6-cyclopentyloxypyridin-3-yl)methyl]-3-[[(6-cyanopyridin-3-yl)carbonyl]amino]pyrrolidine; (3R)-1-[(4-cyanophenyl)[6-(3-pentyloxy)pyridin-3-yl]methyl]-3-[[(6-cyanopyridin-3-yl)carbonyl]amino]pyrrolidine; and (3R)-1-[(4-cyanophenyl)[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]methyl]-3-[[(6-cyanopyridin-3-yl)carbonyl]amino]pyrrolidine or a pharmaceutically acceptable salt thereof. 